DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

February 27-28, 2019 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 27-28, 2019

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Table of Contents Page

Agenda 4-5

Acronyms 6-11

Wednesday: February 27, 2019

Welcome and Introductions 12-16

Japanese Encephalitis

⬧ Introduction

⬧ Background and Review

⬧ Updated Recommendations for US Travelers

⬧ Accelerated Primary Series in Adults

⬧ Booster dose Recommendations

⬧ Vote

17-26

Anthrax Vaccines

⬧ Introduction

⬧ AV7909 (NuThrax®)

⬧ Pre-Exposure AVA Booster Dose Interval

⬧ Vote

26-42

Influenza

⬧ Introduction

⬧ Surveillance Update

⬧ Vaccine Effectiveness Update

⬧ Afluria® Quadrivalent for Children Aged 6 Through 59 Months

⬧ Inactivated Influenza Vaccine and Spontaneous Abortion in the Vaccine Safety Datalink

⬧ Summary and Work Group Considerations

43-58

Human Papillomavirus Vaccines

⬧ Introduction

⬧ Overview and Background

⬧ Impact and Cost Effectiveness of Mid-Adult HPV Vaccination

⬧ Overview of Health Economic Results From 4 Modeling Groups

⬧ Mid-Adult HPV Vaccination: Patient Values and Acceptability

⬧ Program and Vaccine Provider Surveys

⬧ Work Group Considerations

59-80

Combination Vaccines

⬧ Introduction

⬧ Immunogenicity and Safety of a Pediatric Hexavalent Vaccine

⬧ Hib Vaccines in AI/AN Populations

⬧ Summary and Review of Work Group Considerations

80-91

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Thursday: February 28, 2019

Agency Updates

⬧ Centers for Disease Control and Prevention (CDC)

⬧ Center for Medicare and Medicaid Services (CMS)

⬧ Department of Defense (DoD)

⬧ Department of Veteran’s Affairs (DVA)

⬧ Food and Drug Administration (FDA)

⬧ Heath Resources and Services Administration (HRSA)

⬧ Indian Health Services (I HS)

⬧ National Institutes of Health (NIH)

⬧ National Vaccine Program Office (NVPO)

⬧

91-95

Pneumococcal Vaccines

⬧ Introduction

⬧ PCV1 Direct and Indirect Effects on Serotype 3 Disease

⬧ PCV13 Direct Effects on Pneumonia Hospitalizations in Adults

⬧ Comparison of Economic Analyses of PCV13 Use Among Adults ≥65 Years of Age

⬧ GRADE and Evidence to Recommendations (EtR) for PCV3 Use Among Adults ≥65 Years of Age in 

the Context of Indirect Effects Experienced to Date

95-124

Meningitis Vaccines

⬧ Introduction

⬧ Immunogenicity and Safety of MenB-FHbp Booster Dose

⬧ Immunogenicity and Safety of MenB-4C Booster Dose

⬧ GRADE and Evidence to Recommendations Framework for MenB Booster Doses

⬧ Work Group Interpretation of Data, Considerations, and Next Steps

125-143

Zoster Vaccines

⬧ Introduction

⬧ Zoster Vaccine Update and Supply

⬧ RZV Safety Data

143-151

Hepatitis Vaccines

⬧ Introduction

⬧ Background: HepA Vaccines and Persons with HIV Infection

⬧ GRADE: Use of HepA Vaccines among Persons With HIV Infection

⬧ Evidence to Recommendations Framework: Use of HepA Vaccines among Persons with HIV Infection

152-167

Vaccine Supply 167-168

Certification 169

Membership Roster 170-178

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Acronyms

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABCs Active Bacterial Core Surveillance 

ACA Affordable Care Act 

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices

ACOG American College of Obstetricians and Gynecologists

ACP American College of Physicians 

ADVISE Agent-based Dynamic model for Vaccination and Screening Evaluation

AE Adverse Event

AGW Anogenital Warts 

AHIP America’s Health Insurance Plans

AI/AN American Indian/Alaskan Native 

AIGIV Anthrax Immune Globulin Intravenous 

AIM Association of Immunization Managers 

ALTS Atypical Squamous Cells of Undetermined Significance/Low-Grade 

Squamous Intraepithelial Lesions Triage Study 

Anti-HAV Serum Antibody to Hepatitis A Virus 

Anti-HBsAg Hepatitis B Surface Antigen

Anti-PA IgG Anti-Protective Antigen Immunoglobulin G 

AOA American Osteopathic Association 

APhA American Pharmacists Association 

APN Advanced Practice Nurse

APRN Advanced Practice Registered Nurse

aQIV Adjuvanted Quadrivalent Influenza vaccine 

ARFI Acute Respiratory or Febrile Illness 

ARI Acute Respiratory Illness

ART Antiretroviral Therapy

ASC-US Atypical Squamous Cells of Undetermined Significance

ASTHO Association of State and Territorial Health Officers 

ATS American Thoracic Society 

AVA Anthrax Vaccine Adsorbed 

BAL Bronchial Lavage 

B. anthracis Bacillus anthracis

BLA Biologics License Application 

BMI Body Mass Index

CAIH Center for American Indian Health 

CAP Community-Acquired Pneumonia 

CAPiTA Community-Acquired Pneumonia Immunization Trial in Adults 

CDC Centers for Disease Control and Prevention

CDSi Clinical Decision Support for Immunization 

CER Cost-Effectiveness Ratio

CFR Case Fatality Ratio

CIN2+ Cervical Intraepithelial Neoplasia Grade 2 or Worse

CISNET Cancer Intervention and Surveillance Modeling Network 

CLD Chronic Liver Disease 

CMS Center for Medicare and Medicaid Services

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COI Conflict of Interest 

COID Committee on Infectious Diseases (AAP)

CONACH Committee on Native American Child Health 

COPD Chronic Obstructive Pulmonary Disease

CSTE Council of State and Territorial Epidemiologists 

DC District of Columbia

DFO Designated Federal Official

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DSMB Data Safety Monitoring Board 

DTaP Diphtheria and Tetanus Toxoid and Pertussis 

DVA Department of Veterans Affairs

EB Empirical Bayesian 

ED Emergency Department

ED Effective Dilution 

EGL External Genital Lesions 

EHR Electronic Health Record 

EIS Epidemic Intelligence Service

ELISA Enzyme-Linked Immunosorbent Assay 

EMA European Medicines Agency 

EMR Electronic Medical Record 

ESPID European Society for Paediatric Infectious Diseases 

EtR Evidence to Recommendation 

EU European Union 

EUA Emergency Use Authorization 

FDA Food and Drug Administration

FFS Medicare Fee-For-Service 

FHA Filamentous Hemagglutinin 

FQHC Federally Qualified Health Center 

FRA Focus Reduction Assay 

GAVI Global Alliance for Vaccines and Immunisation

GBS Guillain-Barré Syndrome 

GCC (Tom Harkin) Global Communications Center

GEE Generalized estimating equations 

GI Gastrointestinal 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

HAART Highly Active Antiretroviral Therapy

HBIG Hepatitis B Immune Globulin

HCAP Healthcare-Associated Pneumonia 

HCP Healthcare Personnel / Providers

HCW Healthcare Workers 

HEDIS Healthcare Effectiveness Data and Information Set 

HEMU Health Economics Modeling Unit 

HepA Hepatitis A 

HepB Hepatitis B 

HHS (Department of) Health and Human Services

HI Hemagglutinin Inhibition

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Hib Haemophilus Influenzae Type B

HPV Human Papillomavirus

HPV-IMPACT HPV Vaccine Impact Monitoring Project 

HRSA Health Resources and Services Administration 

hSBA Human Serum Bactericidal Activity 

HZ Herpes Zoster 

ICD International Classification of Diseases 

ICER Incremental Cost-Effectiveness Ratio 

ICU Intensive Care Unit

IDSA Infectious Disease Society of America 

Ig Immunoglobulin

IHS Indian Health Service 

IIS Immunization Information Systems 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

ILINet Influenza-like Illness Surveillance Network 

IM Intramuscular 

IND Investigational New Drug 

IOM Institute of Medicine 

IPD Invasive Pneumococcal Disease 

IRB Institutional Review Board

ISD Immunization Services Division 

ISO Immunization Safety Office

ITT Intention-To-Treat 

IV Intravenously 

IVE Influenza Vaccine Effectiveness 

IVIG Intravenous Immunoglobulin 

JE Japanese Encephalitis

IPV Inactivated Poliovirus 

JE-MB Inactivated Mouse Brain-Derived JE Vaccine 

JE-VC Inactivated Vero Cell Culture-Derived JE Vaccine 

KPNC Kaiser Permanente Northern California 

LAIV Live Attenuated Influenza Vaccine 

LD50 Median Lethal Dose 

LLR Log Likelihood Ratio 

LMP Last Menstrual Period

LMICs Low and Middle-Income Countries 

LSIL Low-Grade Squamous Intraepithelial Lesions 

LTFU Long-Term Follow-Up 

MAE Medically Attended Adverse Event

MAM Mid-Adult Men Study

MedDRA Medical Dictionary for Regulatory Activities 

MenB Meningococcal B

MDHHS Michigan Department of Health and Human Services 

MMP Medical Monitoring Project 

MMWR Morbidity and Mortality Weekly Report

mITT Modified Intent-To-Treat Analysis 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

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NACI National Advisory Committee on Immunization 

NAP National Action Plan 

NAPNAP National Association of Pediatric Nurse Practitioners 

NAS National Academy of Sciences 

NBPP Non-Bacteremic Pneumococcal Pneumonia 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

NCHHSTP National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

NCHS National Center of Health Statistics 

NCI National Cancer Institute 

NCIRD National Center for Immunization and Respiratory Diseases 

NCVIA National Childhood Vaccine Injury Act 

NF Neutralizing Factor 

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NHP Non-Human Primate

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health

NIPP Non-Bacteremic Pneumococcal Pneumonia 

NIS-Child National Immunization Survey-Child 

NIS-Teen National Immunization Survey—Teen

NIS National Inpatient Sample 

NNDSS National Notifiable Diseases Surveillance System 

NNV Number Needed to Vaccinate 

NP Nasopharyngeal 

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office 

NVSN New Vaccine Surveillance Network 

NVT Non-Vaccine Types 

NYC New York City

OASH Office of the Assistant Secretary for Health 

OB-GYN Obstetrician-Gynecologist

OID Office of Infectious Disease 

OMPC Outer Membrane Protein Complex 

OP Oropharyngeal 

PA Protective Antigen 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis

PRP Polyribosyl Ribitol Phosphate 

PICO Population, Intervention, Comparison, Outcomes 

PIDS Pediatric Infectious Disease Society 

PK Pharmacokinetics 

PNP Pediatric Nurse Practitioner

PrEP Pre-Exposure Prophylaxis 

PREVENT Pregnancy Influenza Vaccine Effectiveness Network 

PRNT Plaque Reduction Neutralization Test 

PT Preferred Terms (MedDRA)

PWHIV Persons Living With HIV 

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PWID People Who Inject Drugs 

QALY Quality-Adjusted Life-Year 

QIV Quadrivalent Influenza Vaccine 

RCA Rapid Cycle Analysis

RCT Randomized Controlled Trial

RIV Recombinant Influenza Vaccine 

ROA Route of Administration 

RN Registered Nurse

RNA Ribonucleic Acid 

RR Relative Risk

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction

rRT-PCR Real-Time Reverse Transcription Polymerase Chain Reaction 

RZV Recombinant Zoster Vaccine 

S. pneumoniae Streptococcus pneumoniae 

SAB Spontaneous Abortion

SAE Serious Adverse Event 

SAGE Strategic Advisory Group of Experts on Immunization (WHO)

SAHM Society for Adolescent Health and Medicine 

sBLA Supplemental Biologics License Application 

SC Subcutaneous

SCC Squamous Cell Carcinoma 

SES Socioeconomic Status 

SFHR Small Fragment Homologous Replacement 

SIDS Sudden Infant Death Syndrome 

SMD Standardized Mean Difference

SME Subject Matter Expert

SNiPP Surveillance for Non-invasive Pneumococcal Pneumonia 

SNS Strategic National Stockpile

SSUAD Serotype-Specific Urinary Antigen Detection 

TBE Tick-Borne Encephalitis 

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

TNA Toxin Neutralization Assay

TND Test Negative Design 

TIV Trivalent Influenza Vaccine

UAD Urinary Antigen Detection 

UAT Urinary Antigen Test 

UK United Kingdom

US United States

USPHS US Public Health Service 

USPI US Product Information 

US Flu VE US Influenza Vaccine Effectiveness Network

UTD Up-To-Date 

VA (US Department of) Veteran’s Affairs 

VAERS Vaccine Adverse Event Reporting System

VE Vaccine Effectiveness Efficacy

VE Vaccine Efficacy

VFC Vaccines For Children

VICP Vaccine Injury Compensation Program 

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VLP Virus-Like Particles 

VRBPAC Vaccine and Related Blood Products Advisory Committee 

VSD Vaccine Safety Datalink

VT Vaccine Type 

VT-CAP Vaccine-Type Community-Acquired Pneumonia 

WG Work Group

WHO World Health Organization

VE Vaccine Effectiveness

YF Yellow Fever

ZVL Zoster Vaccine Live 

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José Romero, MD, FAAP 

ACIP Chair 

Amanda Cohn, MD 

Executive Secretary, ACIP / CDC 

Dr. Romero called to order the February 2019 Advisory Committee on Immunization Practices 

(ACIP) and thanked everyone for their attendance.

Dr. Cohn welcomed everyone to the February 2019 ACIP meeting. She indicated that the 

proceedings of this meeting would be accessible to people not in attendance via the World Wide 

Web, and welcomed those who could not attend the meeting in person. She pointed out that 

multiple Centers for Disease Prevention and Control (CDC) staff were present at the entrance to

the room and at the desk outside the room to assist members of the public with questions.

She noted that handouts of the presentations were distributed to the voting ACIP members and 

were made available for others on the tables outside of the auditorium. Additionally, slides were 

made available through a ShareFile link for liaison and ex-officio members. Slides presented 

during this meeting will be posted on the ACIP website approximately three to four weeks after

the meeting. The live webcast also will be posted in about four weeks following the meeting, and 

the meeting minutes are posted to the ACIP website generally within about 120 days following 

the meeting. Minutes from the October 2018 meeting were scheduled to be posted shortly after 

the February 2019 meeting.

To ensure the health and safety of all individuals attending this meeting, Dr. Cohn reviewed a 

few safety regulations. She explained that in the event of an emergency resulting in an 

evacuation, the procedures would be as follows: 

❑ Those sitting in the back of the room behind the ropes were instructed to exit out the rear 

doors and across the bridge the way they came in.

❑ Those sitting in the front of room were instructed to exit through the rear of the room,

turn left, then proceed right down the stairs.

❑ Everyone should locate the blue building marker sign labeled “Conference and Meeting 

Space—GCC, 2nd floor” and group together to ensure all attendees are accounted for.

❑ Once the premises have been secured and an “all clear” has been issued, participants 

would be permitted to re-enter the building and the meeting would resume.

The next ACIP meeting will be convened at CDC on Wednesday and Thursday, Wednesday 

and Thursday, June 26-27, 2019. Registration for all meeting attendees is required and will 

open on the ACIP website shortly. Registration is not required for webcast viewing.

Call To Order, Welcome, Overview / Announcements, & Introductions 

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Dr. Cohn announced the following Liaison and Ex Officio member substitutions:

Liaison Representatives 

❑

❑

Susan Lett MD, MPH would be representing Association of Immunization Managers (AIM)

and Council of State and Territorial Epidemiologists (CSTE)

Dr. Linda O’Neal Eckert will serve as the new American College of Obstetricians and 

Gynecologists (ACOG) member

Ex-Officio Members

❑ Lori Hoffman Hōgg MS, RN, CNS would be representing the Department of Veterans Affairs 

(DVA)

Dr. Cohn then introduced the incoming ACIP Chair and Dr. Romero introduced the four new 

ACIP members and guest attendees:

José Romero, MD

Dr. Romero is the incoming ACIP Chair and will serve in this role for the next 3 years. He was 

an ACIP member from 2014-2018. He is a pediatrician and pediatric infectious disease 

specialist at the University of Arkansas. He brings extensive administrative, vaccine policy, 

clinical, teaching, and research perspective to the ACIP. He has done a remarkable job over the 

years leading several ACIP Work Groups (WGs) as Chair. Dr. Romero responded that this was 

a unique honor and that he was very grateful to have this position. 

Kevin Ault, MD

Dr. Ault is a Professor of Obstetrics and Gynecology at the University of Kansas School of 

Medicine. He was a Liaison representative to ACIP from ACOG from 2013-Present. He currently 

is a member of ACIP Influenza WG.

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Stephan Gravenstein, MD, MPH

Dr. Gravenstein is an Academic and Clinical Geriatrician at Brown University School of Medicine 

and School of Public Health. He has extensive immunization research experience across the 

lifespan, with a special focus on immunization issues in older adults.

Veronica Valentine McNally, JD

Veronica Valentine McNally will serve as the Consumer Representative to ACIP. She is 

President and CEO of the Franny Strong Foundation, which was established in memory of her 

infant daughter and provides education about vaccinations.

H. Keipp Talbot, MD, MPH

Dr. Keipp Talbot is an Internist and Infectious Disease Specialist at Vanderbilt University. She 

also brings to ACIP immunization research experience across the lifespan, with a special focus 

on immunization issues in older adults. Previously, she was a member of the ACIP 

Pneumococcal WG.

Guest Attendees at This Meeting

❑

❑

Dr. Alejandro Cravioto, Chair, World Health Organization (WHO) Strategic Advisory Group 

of Experts on Immunization (SAGE)

Dr. Jon Abramson, Chair, Global Alliance for Vaccines and Immunisation (GAVI) Vaccine 

Investment Strategy Steering Group

Dr. Cohn indicated that as stated in the ACIP charter, the purpose of the ACIP committee is to 

deliberate on the use of vaccines to control disease in the United States (US), including 

considerations of disease epidemiology and burden of disease, vaccine efficacy and 

effectiveness, vaccine safety, the quality of evidence reviewed, economic analyses, and 

implementation issues:

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❑

❑

“The committee may revise or withdraw their recommendations regarding a particular 

vaccine as new information on disease epidemiology, vaccine effectiveness of safety, 

economic consideration or other data become available.”

“Under provisions of the Affordable Care Act (ACA) . . . immunization recommendations 

of the committee that have been adopted by the Director of the CDC must be covered by 

applicable health plans”

ACIP is, at its heart, a public body. Engagement with the public and transparency in ACIP’s

processes is vital to the Committee’s work. As part of ACIP’s commitment to continuous 

improvement, this meeting features changes to strengthen ACIP’s oral and written public 

comment process. These changes are designed to accommodate increased public interest in 

ACIP’s work, maximize opportunities for comment, make public comment more transparent and 

efficient, and create a fair process for assigning limited oral public comment time. Dr. Cohn took 

a couple of minutes to outline these changes for this meeting. As always, ACIP is dedicated to 

continuous improvement and welcomes feedback on ways they can continue to strengthen 

ACIP’s processes and maximize engagement with the public.

First, Dr. Cohn addressed changes to ACIP’s oral public comment process. In previous 

meetings, ACIP would hold multiple, short public comment periods over the course of the 

meeting’s two days and people would sign up for public comment on site at the day of the 

meeting. With increased public interest in commenting at ACIP meetings, ACIP wanted to 

improve this process to provide more time for public comment, make the process for signing up 

for comment more efficient, and create a fair way to determine public speakers when there were 

more people requesting to speak than could be accommodated in the meeting’s limited time.

For this meeting, the following improvements to ACIP’s public comment process were made:

❑

❑

More Time: Rather than multiple short periods across two days, there is now a single, 

75-minute public comment period at the end of the first day of the meeting and before 

any scheduled votes. This change reserves more time for public comment than in 

previous meetings, and allows speakers to hear all the presentations related to an ACIP 

vote before their comments.

Clearer Registration Process: To create a fairer and more efficient process for 

requesting to make an oral comment, ACIP now asks that people interested in making 

an oral comment submit a request online in advance of the meeting. Priority is given to 

these advance requests. If more people request to speak than can be accommodated, a 

blind lottery will be conducted to determine who the speakers will be. Speakers selected 

in the lottery will be notified in advance of the meeting. Public comment speakers for this 

meeting were instructed to sign in with Noah Aleshire at the information table outside the 

main auditorium so that ACIP would know they were present.

Some elements of the previous process have been maintained. As with previous comment 

periods, speakers will be limited to three-minutes to make their comments. It is critical that 

speakers stay within this time to ensure that all public commenters have an opportunity to 

speak. A lighted timer will be displayed on the screen so that the speakers will know when their 

time has expired. As with previous meetings, the ACIP Chair has discretion to recognize 

individuals to provide scientific and technical information that is relevant to the Committee’s 

deliberations at any time during the meeting. This is not an alternative to the public comment 

process. Rather, it is an opportunity for the Committee to obtain relevant scientific and technical 

information from individual experts and stakeholders to inform its discussions.

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Substantial improvements also have been made to ACIP’s written comment process. These 

changes were made based on feedback from the public asking for more time and the ability to 

submit more detailed written comments. Previously, public comments were submitted via email 

to CDC, with length limited to one-page and comments required to be submitted before to the 

meeting. For this and subsequent meetings, ACIP is using a docket on regulations.gov where 

any member of the public can submit a written comment. This is a substantial improvement, as 

this new process allows for the ability to submit longer comments and the ability to include 

attachments, visibility of the comments to the public, and a longer window for comment 

submission. Comments may now be submitted up to 48 hours following the end of the meeting. 

All comments submitted within 72 hours prior to the meeting will be made available to the ACIP 

members prior to the meeting.

At the time of this meeting, the docket was still open. Using docket ID CDC-2019-0002, those 

interested were invited to submit a comment at regulations.gov. Dr. Cohn indicated that the 

docket would remain open for 48 hours following the end of the meeting. This information also

can be found in the Federal Register notice announcing ACIP meetings and on the ACIP 

meeting website. She encouraged everyone to access and read the public comments posted.

As noted in the ACIP Policies and Procedures manual, members of the ACIP agree to forgo 

participation in certain activities related to vaccines during their tenure on the committee. For 

certain other interests that potentially enhance a member’s expertise while serving on the 

committee, CDC has issued limited conflict of interest (COI) waivers. Members who conduct 

vaccine clinical trials or serve on data safety monitoring boards (DSMBs) may present to the 

committee on matters related to these vaccines, but are prohibited from participating in 

committee votes on issues related to those vaccines. Regarding other vaccines of the 

concerned company, a member may participate in discussions, with the provision that he/she 

abstains on all votes related to the vaccines of that company. At the beginning of each meeting, 

ACIP members state any COIs.

Detailed instructions for submission of names of potential candidates to serve as ACIP 

members will be added to the ACIP website shortly. A transition is being made to an online 

application process, which is anticipated to make the process more efficient and easier for 

members to apply for nomination. Applications for ACIP membership are due no later than July 

1, 2019 for the 4-year term beginning July 2020.

Dr. Romero conducted a roll to determine whether any ACIP members had COIs. Dr. 

Gravenstein declared COIs related to Sanofi, Seqirus, and Merck. Dr. Romero then requested 

that the Liaison and Ex Officio members introduce themselves. A list of Members, Ex Officio

Members, and Liaisons is included in the appendixes at the end of the full minutes from the 

February 2019 ACIP meeting.

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Introduction

Chip Walter, MD

Chair, ACIP Flavivirus Vaccines WG

Dr. Walter reminded everyone that the Japanese Encephalitis (JE) Vaccine WG’s objectives are 

to: 1) review newly available safety and immunogenicity data for inactivated Vero cell culturederived JE vaccine (JE-VC); 2) review epidemiology and risk of JE in travelers; 3) review ACIP 

recommendations for use of JE vaccine in consideration of updated data; and 4) update 

Morbidity and Mortality Weekly Report (MMWR) Recommendations and Reports.

WG presentations to ACIP during the October 2018 session included the following topics:

❑

❑

❑

➢

➢

Evidence to Recommendations (EtR) framework for updated JE vaccine recommendations

Accelerated dosing schedule data in adults

Booster dose recommendations

Strengthen current permissive recommendation

Expand to include children aged <17 years

Dr. Walter indicated that this session would include the following presentations in anticipation of 

taking a final vote:

❑

❑

➢

➢

➢

❑

Background and review of JE and JE vaccine

Review and vote on

Updated recommendations for U.S. travelers

Accelerated primary series in adults

Booster dose recommendations 

Conclusion and next steps

Background and Review of JE and JE Vaccine

Dr. Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

Dr. Hills began her presentation with a brief background and review of JE and JE vaccine. JE is 

caused by a mosquito-borne flavivirus that occurs in most of Asia and parts of the Western 

Pacific, and is the leading vaccine-preventable cause of encephalitis in Asia. Most JE virus 

infections are asymptomatic with fewer than 1% of infected people developing neurological

disease. However, when disease does occur it is often severe. Overall, about 20% to 30% of 

patients die and 30% to 50% of survivors have significant neurologic, cognitive, or behavioral 

sequelae. There is no specific antiviral therapy, and treatment consists of supportive care1. 

Currently, even with national vaccination programs in some endemic countries, there are still an 

Japanese Encephalitis Vaccine

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estimated 68,000 JE cases annually in Asia, with an overall incidence for all age groups of 

approximately 1.8 cases per 100,000 population. The highest risk for infection is in rural, 

agricultural areas because the primary breeding site for the main vector is rice fields2[

1Vaughn 

DW. Epidemiol Rev 1992; 2Campbell GL, et al. Bull World Health Organ 2011].

For most travelers to Asia, the risk for JE is very low but varies based on travel destination, 

duration, season, activities, and accommodations. A JE vaccine was first licensed in the US in 

1992. In the 25 years from 1992 through 2017, only 12 JE cases were identified among US 

travelers or expatriates. Based on these 12 reported JE cases and 4 to 5 million US citizen trips 

to Asia annually, the estimated risk for travelers is less than 1 case per million trips to Asia. 

Travelers with longer trips or increased rural and outdoor exposures are at higher risk of 

acquiring JE virus infection. Among the 12 US traveler cases, 8 (67%) had traveled for a month 

or longer, 3 (25%) had traveled for less than a month but spent at least one night in a rural area, 

and 1 (8%) traveled for less than one month but there was no information on this individual’s

itinerary or activities [Hills et al. CDC Yellow Book 2018].

JE-VC, manufactured by Valneva as IXIARO®, is the only JE vaccine currently licensed and 

available in the US. The vaccine was licensed for adults 17 years of age and older in 2009, and 

the licensure was subsequently extended to children ages 2 months and older in 2013. The 

primary series is 2 doses administered 28 days apart. ACIP recommendations for a booster 

dose for adults at least 1 year after the primary series were approved in 2011. Dr. Hills noted 

that she would discuss booster doses for children later in the session.

There are no efficacy data for IXIARO®. However, there is an established immunologic correlate 

of protection which is a JE virus 50% plaque reduction neutralization test (PRNT50) titer of ≥10.

The vaccine was licensed based on a non-inferior neutralizing antibody response compared 

with a licensed mouse brain-derived JE vaccine [Hombach J. Vaccine 2005; Markoff L. Vaccine 

2000].

Following licensure of JE-VC for adults in 2009, ACIP approved recommendations for use of JE 

vaccine in US travelers. In 2013, following licensure of JE-VC for children, a Grading of 

Recommendation Assessment, Development and Evaluation (GRADE) analysis was performed 

and JE vaccine recommendations were reviewed. The recommendations were extended to 

children, but no other changes to the recommendation were considered necessary [CDC. 

MMWR Rec Rep 2010; CDC. MMWR Morb Mortal Wkly Rep 2013].

The current review of the JE vaccine recommendations for travelers is a routine review in 

consideration of new safety, immunogenicity, and traveler risk data. As part of this review, the 

JE Vaccine WG has prepared an updated MMWR Recommendation and Reports document that 

incorporates previously published policy notes and new data indications and dosing schedules. 

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Updated Recommendations for US Travelers

❑

❑

❑

❑

Dr. Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

Dr. Hills indicated that as Dr Walter mentioned earlier, ACIP would be asked to vote on three 

topics in regard to JE vaccine during this meeting, the first of which would be the updates to the 

JE vaccine recommendations for US travelers. The changes from the current JE-vaccine 

recommendations are minor. In summary they are as follows:

Inclusion of additional information on the factors that increase JE risk to help healthcare 

providers identify travelers who might be at high risk of JE virus infection based on their 

planned itinerary and to assist with decision-making regarding who should be vaccinated

Longer-term travel is no longer defined as a specific cut-off of 1 month or longer

Consideration of vaccination for travelers to an area with an ongoing JE outbreak has

been removed 

Minor wording changes have been made to address questions that have been raised 

about the wording of the existing recommendations, such as changing “expatriates” to 

“persons moving to a JE-endemic country to take up residence”

ACIP would be asked to vote on these slightly modified JE vaccine recommendations for US 

travelers. However, the WG felt that the additional information provided as part of the overall JE

vaccine recommendations would be essential for providing context. Although ACIP members 

reviewed this information in the background materials that were sent around, Dr. Hills reviewed

the complete JE vaccine recommendations section of the MMWR document. The 

recommendations section begins with the following:

“JE is a very low risk disease for most US travelers to JE-endemic countries. However, 

some travelers will be at increased risk of infection based on their planned itinerary. 

Factors that increase the risk of JE virus exposure include: 1) longer duration of travel; 

2) travel during the JE virus transmission season; 3) spending time in rural areas; 4) 

participating in extensive outdoor activities; and 5) staying in accommodations without 

air conditioning, screens, or bed nets.”

Accompanying the recommendations is a box that provides more information on these five risk 

factors to assist healthcare providers in advising patients on what factors increase their risk. The 

first two sections of the box explain “Duration” and “Season.” The “Duration” section provides an 

explanation that in terms of duration, the highest incidence of disease occurs in longer-term 

travelers, there is not a specific duration that puts a traveler at risk, but longer-term travel 

increases the likelihood of exposure to infected mosquitos, and that longer-term travel includes 

cumulative periods in endemic areas. It then describes that JE virus transmission can be 

seasonal or year-round and points to resources to assist in understanding this further. The 

“Location” section outlines the settings where the highest risk occurs and other potential 

concerns related to the location of travel, the “Activities” section discusses the higher risk with 

outdoor activities and provides examples, and the “Accommodations” section provides more 

details on accommodations that are likely to increase the risk of mosquito exposure:

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Duration

• Highest incidence of disease has been reported among longer-term travelers. 

• Although no specific duration of travel puts a traveler at risk for JE, longer-term travel increases the likelihood that a traveler 

might be exposed to an infected mosquito.

• Longer-term travel includes cumulative periods in endemic areas, such as frequent travelers, and persons residing in urban 

areas who are likely to visit higher risk rural areas.

Season

• JE virus transmission occurs seasonally in some areas, and year-round in other areas.

• Information on expected JE virus transmission by country is available on the CDC website (see Japanese encephalitis chapter 

in CDC Health Information for International Travel [the Yellow Book]). These data should be interpreted cautiously because JE 

virus transmission varies within countries and from year to year.

Location

• Highest risk occurs from mosquito exposure in rural or agricultural areas.

• Mosquitoes that transmit JE virus typically breed in flooded rice fields, marshes, and other stagnant collections of water. 

• Some cases have been reported among travelers to coastal areas or resorts located in or adjacent to rural or rice growing 

areas.

• JE can occur in large, focal outbreaks indicating extensive active JE virus transmission in those areas.

Activities

• The mosquitoes that transmit JE virus feed most often in the outdoors, particularly from sunset through dawn, so examples of 

activities that increase risk include:

o Outdoor recreation such as camping, hiking, trekking, biking, rafting, fishing, hunting, or farming.

o Spending substantial time outdoors, especially during the evening or night.

Accommodations

• Accommodations without air conditioning, screens, or bed nets increase risk of mosquito exposure.

The recommendations section then moves on to say:

“Healthcare providers should assess each traveler’s risk for mosquito exposure and JE 

virus infection based on their planned itinerary, and discuss ways to reduce their risk. All 

travelers to JE-endemic countries should be advised to take precautions to avoid 

mosquito bites to reduce the risk for JE and other vector-borne diseases. These 

precautions include using insect repellent, permethrin-impregnated clothing, and bed 

nets, and staying in accommodations with screened or air-conditioned rooms.

For some people who might be at increased risk for JE based on travel duration, season, 

location, activities, and accommodations, JE vaccine can further reduce the risk for 

infection. The decision whether to vaccinate should be individualized and weigh the: 1) 

risks related to the specific travel itinerary, 2) likelihood of future travel to JE-endemic 

countries, 3) high morbidity and mortality of JE when it occurs, 4) availability of an 

effective vaccine, 5) possibility, but low probability, of serious adverse events following 

vaccination, and 6) traveler’s personal perception and tolerance of risk.”

Dr. Hills noted that this is the wording ACIP members would be asked to vote on, although she 

emphasized that it is important to consider this language in the broader context of the 

information she just presented, which also will appear in the recommendations section of the 

MMWR document. The wording is:

“JE vaccine is recommended for persons moving to a JE-endemic country to take up 

residence, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent 

travelers to JE-endemic areas.

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JE vaccine also should be considered for shorter-term (e.g., less than 1 month) travelers 

with an increased risk of JE based on planned travel duration, season, location, 

activities, and accommodations . Vaccination also should be considered for travelers to 

endemic areas who are uncertain of specific duration of travel, destinations, or activities. 

JE vaccine is not recommended for travelers with very low risk itineraries, such as 

shorter-term travel limited to urban areas or travel that occurs outside of a well-defined 

JE virus transmission season.”

JE-VC Accelerated Primary Series for Adults Aged 18-65 Years

Dr. Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

The second topic Dr. Hills reviewed during this session for an ACIP vote was the accelerated 

schedule for JE-VC for adults aged 18 through 65 years. Although these data were presented to 

ACIP during the October 2018 and previous ACIP meetings, she briefly reviewed them before 

the vote.

In terms of the timeline of relevant events in regard to this topic, the Food and Drug 

Administration (FDA) approved JE-VC for use as a 2-dose primary series administered in the 

standard schedule at 0 and 28 days in March 2009. In October 2015, the manufacturer 

presented data to ACIP for an alternate accelerated primary series at 0 and 7 days in adults. In 

December 2017, the manufacturer submitted the Biologics License Application (BLA)

amendment to the FDA. In October 2018, the FDA approved the accelerated primary series and 

the WG re-presented these data to ACIP.

The primary data supporting the accelerated schedule came from a randomized trial among 

adults aged 18 through 65 years. The study was conducted at seven study sites in Europe. JEVC was administered with rabies vaccine in an accelerated or conventional schedule, and noninferiority of the accelerated 0 and 7 day schedule compared with the 0 and 28 day conventional 

schedule was assessed1. Some additional data on a shorter primary series schedule came from 

a previous Phase 2 study in adults. In this trial, JE-VC was administered on a day 0, 14 and 28 

day schedule or a 0 and 28 day schedule. For participants randomly assigned to the group that 

received the 0, 14 and 28 day schedule, blood was collected from participants prior to their third 

vaccination on day 28, meaning there are at 14 days after a 0 and 14 day schedule2[Jelinek T. 

J Travel Med 2015; Lyons A. Vaccine 2007].

In terms of the results from the primary study supporting the accelerated schedule, 99% of

subjects who received the 0 and 7 day schedule were seroprotected at 28 days after dose 2 

compared with 100% who were seroprotected after 2 doses when the doses were administered 

28 days apart. The geometric mean titer (GMT) in the accelerated schedule group was higher 

than in the conventional schedule group. At 1 year after the second JE-VC dose,

94% of subjects who received the 2 doses 7 days apart and 86% of those who received the 2 

doses 28 days apart were seroprotected, and the GMT remained higher in the accelerated 

schedule group [

1Jelinek T. J Travel Med 2015; 2Cramer JP. J Travel Med 2016;

3https://clinicaltrials.gov].

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Regarding the additional data from the Phase 2 study, 96% of subjects who received 2 JE-VC 

doses on days 0 and 14 were seroprotected at 14 days after the second dose and the GMT was 

328, which was almost the same as the seroprotection rate and GMT in the subjects who 

received the 2 doses on days 0 and 28 [Lyons A. Vaccine 2007].

The dose of JE-VC varies by age group and the accelerated primary series schedule data are 

only approved for adults ages 18 to 65 years. For children aged 2-35 months, the dose will be 

two 0.25mL doses administered on days 0 and 28. For children and adolescents aged 3-17 

years, two 0.5mL doses are administered on days 0 and 28. For adults aged 18-65 years, the 

dose remains 0.5mL, but the second primary series dose can be administered from 7-28 days 

after the first dose. For adults aged >65 years, two 0.5mL doses are administered on days 0 

and 28.

The vote for this section was for the proposed new recommendation for an accelerated 

schedule in adults aged 18-65 years. The wording is as follows:

“In adults aged 18-65 years, the primary vaccination schedule is two doses administered 

on days 0 and 7-28”

JE-VC Booster Doses

Dr. Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

The final topic Dr. Hills reviewed for the vote was JE-VC booster doses. As a reminder, in 

September 2010, the FDA approved a JE-VC booster dose for adults aged 17 years and older.

ACIP subsequently approved a booster dose recommendation for adults. In February 2016, the 

manufacturer presented data to ACIP for a booster dose in children. In June 2017, the 

manufacturer submitted to the FDA a BLA amendment for a pediatric booster dose. In April 

2018, the FDA approved the pediatric booster dose. In October 2018, the WG re-presented 

relevant booster dose data to ACIP. The current ACIP recommendation for a JE-VC booster 

dose is for adults aged 17 years and older is, “If the primary series of JE-VC was administered 

more than 1 year previously, a booster dose may be given before potential JE virus exposure” 

[CDC. MMWR Morb Mortal Wkly Rep 2011]. 

The topics for consideration in regard to changes to the recommendation were to lower the 

recommended age for a booster dose to include children, and to strengthen the current 

permissive booster dose recommendation. The supporting data for each topic were presented 

to ACIP during previous meetings and draft recommendations were presented in October 2018. 

Dr. Hills provided a brief review of the supporting data for each topic . For the pediatric booster 

dose recommendation, the supporting data come from one open label randomized trial 

conducted among children aged 14 months through 17 years. The study was conducted in the 

Philippines, which is a JE endemic country. It included 300 children randomized to receive or 

not receive a booster dose of JE-VC. For the 150 randomized to receive the booster dose, it 

was administered at 11 months after the second dose of the 2-dose primary JE-VC series1. 

Among these children who received the booster dose, 100% were seroprotected at 28 days 

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after the booster dose with a GMT over 2000. At 2 years after the booster, 100% remained 

seroprotected and the GMT was 350 [Kadlecek V. Pediatr Infect Dis J. 20182; Kadlecek V. 

Pediatr Infect Dis J. 2018]. The WG concluded that the current booster dose recommendation 

for adults should be modified to include children.

The second booster dose topic Dr. Hills briefly reviewed were the data supporting the 

strengthening of the current booster dose permissive recommendation stating, “if the primary 

series of JE-VC was administered >1 year previously, a booster dose may be given before 

potential JE virus exposure.” In the three studies that were the basis for this recommendation, 

the data showed that at 12-15 months after the 2-dose primary JE-VC series, 58%-83% of 

subjects were seroprotected. These studies were conducted in Europe where tick-borne 

encephalitis (TBE) vaccine is available. TBE virus is a flavivirus related to JE virus, and there 

was concern that there might have been a boosting effect of TBE vaccine which could explain 

some of the variability in study results. As a result, the manufacturer conducted a post hoc 

analysis that stratified subjects by TBE vaccination status [Schuller E. Vaccine 2008; DubischarKastner K. Vaccine 2010; Eder S. Vaccine 2011; Dubischar K. ACIP presentation. February 

2016].

That analysis showed that if subjects had received TBE vaccine before or after JE-VC, 

seroprotection rates over the following 5 years ranged from 92% at 1 year to 86% at 5 years. 

However, if subjects had not received TBE vaccine, seroprotection rates were lower, ranging 

from 75% at 1 year down to 64% at 5 years. In the group who had received TBE vaccine, 

geometric mean titers were also higher at each time point [Dubischar K. ACIP presentation. 

February 2016].

The WG concluded that after a 2-dose primary series, long-term JE seroprotection rates are 

lower in those not administered TBE vaccine compared with those administered TBE vaccine. 

TBE vaccine is not available in the US, and other flavivirus vaccines such as yellow fever (YF) 

vaccine are not routinely administered with JE-VC. Therefore, among US travelers, duration of 

protection following a booster dose of JE-VC is likely to be most similar to the subjects not 

administered TBE vaccine who had lower seroprotection rates through 5 years. Based on these 

data, the WG recommended that the permissive booster dose recommendation should be 

strengthened from “may be given” to “should be given.”

In summary, the final vote for an updated recommendation for a JE-VC booster dose will apply 

to both children and adults and will read as follows: 

“A booster dose (i.e., third dose) should be given at ≥1 year after completion of the 

primary JE-VC series if ongoing exposure or re-exposure to JE virus is expected.” 

In terms of next steps, the draft MMWR Recommendations and Reports on JE vaccine for US 

travelers was circulated to ACIP members prior to this meeting, and the WG expected to be 

able to finalize and move to publication of the document after this meeting. Dr. Hills concluded 

that with the topics addressed in the votes during this session and the publication of the MMWR, 

the objectives for the JE Vaccine WG would all have been addressed and all activities 

completed. Therefore, the WG expects to discontinue the JE Vaccine WG meetings.

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Discussion Points

Dr. Bernstein inquired as to whether there are any data for multiple boosters over time.

Dr. Hills responded that in the adult data following a single booster, there are seroprotection 

data through 6 years which show 96% protection. There are not additional data beyond that, so 

there are no recommendations for additional booster doses.

Dr. Romero pointed out that one consideration for the vote would be to mention that this is for 

both children and adults, because the recommendations over time have changed.

Dr. Hunter said he assumed the recommendation for the booster did not decrease the amount 

of vaccine available in permanent residents of the high risk areas, because a small amount of 

vaccine would be used.

Dr. Hills responded that the vaccine licensed in the US is not used in the national immunization 

programs in endemic countries because there are additional vaccines. A live-attenuated vaccine 

is produced in China that is used most extensively in JE-endemic countries. There also is a 

chimeric vaccine that is not licensed in the US that is available in endemic countries. JE-VC is 

licensed in some of the endemic countries and might be used in the private sector, but is not 

used in the very large national immunization programs, so there will be no impact there.

Dr. Walter asked whether three different motions would be needed, given that there were three 

separate recommendations. 

Dr. Cohn confirmed that three votes would be needed. She explained that the process for the 

vote would be for ACIP members to propose/second a motion to vote, further discussion would

then be entertained, and the vote would be stayed until the afternoon following public comment.

During the JE session, Dr. Romero read each of the proposed recommendations into the 

record. During the voting session in the afternoon, Dr. Hills re-read the proposed 

recommendations before the vote with the incorporation of an suggested revisions. The 

proposed recommendations, motions, additional discussion, and the vote are combined as 

follows for ease of reading:

#1: Proposed JE Vaccine Recommendations

“JE vaccine is recommended for persons moving to a JE-endemic country to take up 

residence, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent 

travelers to JE-endemic areas.

JE vaccine also should be considered for shorter-term (e.g., <1 month) travelers with an 

increased risk of JE based on planned travel duration, season, location, activities, and 

accommodations. Vaccination also should be considered for travelers to endemic areas 

who are uncertain of specific duration of travel, destinations, or activities. 

JE vaccine is not recommended for travelers with very low risk itineraries, such as 

shorter-term travel limited to urban areas or travel that occurs outside of a well-defined 

JE virus transmission season.”

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Motion/Further Discussion

Dr. Frye proposed a motion to vote on JE Vote #1 as stated, which was seconded by Dr. 

Atmar. 

No further discussion was posed.

Motion/Vote #1: Proposed JE Vaccine Recommendations

Dr. Frye proposed a motion to vote on JE Vote #1 as stated, which was seconded by Dr. Atmar. 

The motion carried with 15 affirmative votes, 0 negative votes, and 0 abstentions. The 

disposition of the vote was as follows:

15 Favored: Atmar, Ault, Bernstein, Ezeanolue, Gravenstein, Frey, Hunter, Lee, McNally, 

Moore, Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

#2: Proposed New Recommendation for Primary Series Schedule in Adults Aged 18-65 

Years

“In adults aged 18–65 years, the primary vaccination schedule is two doses 

administered on days 0 and 7–28.”

Motion/Further Discussion

Dr. Walter made a motion vote on the second recommendation as stated, which was 

seconded by Dr. Moore. 

Dr. Lee thought it would be beneficial to have additional information if possible postrecommendation on safety surveillance for the accelerated schedule, it would add to the 

benefit-risk balance over time.

Motion/Vote #2: Proposed New Recommendation for 

Primary Series Schedule in Adults Aged 18–65 Years

Dr. Walter made a motion to vote on the second recommendation as stated, which was 

seconded by Dr. Moore. The motion carried with 15 affirmative votes, 0 negative votes, and 0 

abstentions. The disposition of the vote was as follows:

15 Favored: Atmar, Ault, Bernstein, Ezeanolue, Gravenstein, Frey, Hunter, Lee, McNally, 

Moore, Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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#3: Proposed New Recommendation for JE-VC Booster Dose

“A booster dose (i.e., third dose) should be given at ≥1 year after completion of the 

primary JE-VC series if ongoing exposure or re-exposure to JE virus is expected.” 

Motion/Further Discussion

Dr. Moore made a motion to vote on the third recommendation as proposed, which was 

seconded by Dr. Walter.

Dr. Szilagyi suggested adding, “for children and adults” because it differs from the other 

recommendation.

Motion/Vote #3: Proposed New Recommendation for JE-VC Booster Dose

Dr. Moore made a motion to vote on the third recommendation as proposed, which was 

seconded by Dr. Walter. The recommendation was revised to read, “For adults and children, a

booster dose (i.e., third dose) should be given at ≥1 year after completion of the primary JE-VC 

series if ongoing exposure or re-exposure to JE virus is expected.” The motion carried with 15

affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

15 Favored: Atmar, Ault, Bernstein, Ezeanolue, Gravenstein, Frey, Hunter, Lee, McNally, 

Moore, Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Introduction

David S. Stephens, MD, FIDSA

ACIP Anthrax Vaccine Work Group (WG)

Dr. Stephens reminded everyone that the Anthrax Vaccine WG was reconvened in March 2017 

to discuss new data published since the last review in 2010. The US government stockpiles

medical countermeasures, including anthrax vaccine, and CDC provides guidance for vaccine 

use and other aspects of preparedness should there be a wide-area release of Bacillus 

anthracis (B. anthracis) spores. The WG considered the body of evidence since the last review 

in 2010 for policy changes to optimize the use of anthrax vaccine for use prior to and following a 

wide-spread release of B. anthracis spores.

The topics of focus for this session included an informational session on the use of a new 

anthrax vaccine (AV7909) for postexposure prophylaxis (PEP), and policy vote on a change to 

the pre-exposure prophylaxis (PrEP) booster dose interval for persons who are not at current 

high risk of exposure to anthrax. The ACIP Anthrax WG will stand down after the MMWR policy 

update is published, which is anticipated to occur within the next 3 months. It is anticipated that 

the WG will be reactivated in the 2021-2022 timeframe to review new data from studies on 

Anthrax Vaccine

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AV7909 currently underway or planned to start later in 2019, as well as potentially new data on 

booster dose interval of greater than 3 years for PrEP. 

Next Generation Anthrax Vaccine: AV7909

William Bower, MD, FIDSA

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention

Dr. Bower indicated that the purpose of this session was to present information on the use of a 

new anthrax vaccine, AV7909, for PEP following exposure to aerosolized B. anthracis spores 

when anthrax vaccine adsorbed (AVA) availability is limited. Currently, AVA is the only approved 

vaccine with an indication for use as PEP in persons with exposure to aerosolized B. anthracis

spores. These data compare the immunogenicity and safety of AV7909 administered as a 2-

dose series 2 weeks apart compared to AVA administered as a 3-dose series 2 weeks apart.

This is a unique policy issue for the ACIP Committee. AV7909 is not currently a licensed 

vaccine and would only be available for emergency use. The WG chose present information on 

this vaccine to ACIP during this meeting because they believe it is important to review the data 

in this open forum prior to a public health emergency. In the event of an anthrax incident, an 

emergency meeting of ACIP will be convened to review these data plus any new data generated 

since this meeting and ask ACIP’s recommendation regarding the use of this vaccine under an 

Emergency Use Authorization (EUA).

To set the stage, Dr. Bower began by providing some background information important for 

understanding the use of anthrax vaccine for PEP. There are four types of anthrax categorized 

by the route of spore entry into the body. Spores introduced through skin lesions lead to 

cutaneous anthrax. It has an incubation period of between 1 and 14 days and can have a fatality 

rate as high as 24% if untreated. Spores that are introduced through the gastrointestinal tract 

lead to ingestion anthrax. It also has an incubation period of between 1 and 14 days and can 

have a fatality rate as high as 40% even with treatment. Spores inhaled into the lungs lead to 

inhalation anthrax. After gaining entry, B. anthracis spores are thought to either germinate 

locally or to be transported by phagocytic cells to regional lymph nodes, where they can 

germinate. Spores inhaled into the lungs may not germinate immediately and incubation periods 

of up to 43 days have been documented. This is why vaccine is recommended after exposure to 

aerosolized spores to protect against the late germination of spores after antimicrobial 

prophylaxis has been discontinued. Inhalation anthrax mortality rates have improved in the age 

of modern critical care medicine, but are still as high as 47% even with treatment. Injection 

anthrax is a newly described form which has only been documented in Northern Europe. It has 

only been seen in injection drug users who used heroin contaminated with spores.

Anthrax is usually a disease of herbivores that ingest spores while grazing. Humans are 

secondarily infected by handling infected carcasses or consuming contaminated meat.

Historically, inhalation anthrax was seen as an occupational risk in textile mills that processed 

animal hides that were contaminated with spores. Today, rare cases of inhalation anthrax are 

seen in persons related to work or hobbies that involve animal hides, such as drum making.

However, it is known that B. anthracis is one of the most likely pathogens to be used as a 

bioweapon. B. anthracis spores are relatively easy to produce, can be stored for a long time,

and can be dispersed in the air through a variety of means. In addition, inhalation anthrax is 

highly lethal and the spores may survive in the environment for greater than 40 years. A widearea release of aerosolized spores over a densely populated area could cause widespread 

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illness and death among unprotected persons. In 1979, an accidental release of anthrax spores 

from a Soviet bioweapons laboratory in Sverdlosk resulted in the deaths of at least 60 persons 

in the community that was downwind of the facility. In 2001, B. anthracis spores sent through 

the US Postal Service (USPS) resulted in at least 22 cases of anthrax and 5 deaths.

To illustrate the potential public health emergency that a release of B. anthracis spores could 

produce, the following graphic using data from US government sources shows a hypothetical 

release of aerosolized B. anthracis spores along a commuter rail line in a major metropolitan 

city. This model predicts that the spore plume drifting over a densely populated area could 

potentially expose hundreds of thousands of persons to spores who would require a 

combination of antimicrobials and vaccine PEP to prevent disease:

PEP for anthrax requires early use of antimicrobials to prevent disease until the vaccine has a 

chance to produce a protective immune response. Currently, the only licensed anthrax vaccine 

is AVA, which is FDA-approved for both PrEP and PEP of anthrax. Doxycycline, penicillin G, 

ciprofloxacin, and levofloxacin are FDA-approved for the antimicrobial component of PEP to 

prevent inhalation anthrax. The manufacturer of AVA is Emergent BioSolutions. AVA is a cellfree filtrate derived from avirulent B. anthracis growth in culture. The primary antigen is 

protective antigen (PA). AVA contains aluminum as an adjuvant and two preservatives. AVA 

primes the immune system to recognize and block PA, which is common to all anthrax strains. 

Vaccine efficacy against numerous anthrax strains has been demonstrated in many animal 

studies. For PEP, AVA is given by the subcutaneous (SC) route as a one-month primary series 

at 0, 2, and 4 weeks in conjunction with 60 days of antimicrobials.

AVA was last reviewed by ACIP in 2009 and recommendations were published in 2010. ACIP 

recommended three subcutaneous doses at 2 week intervals. At the time, AVA did not have an 

indication for PEP, so the vaccine would have been used under an EUA protocol. This 

recommendation extended to pregnant and breastfeeding women as well. The data that 

supported the safety for use in these populations came from the use of the vaccine for PrEP. 

There were no data for use in children, but the committee felt that given the high risk of mortality 

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related to anthrax that the vaccine could be given to children under an Investigational New Drug

(IND) protocol.

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Since the last ACIP review of anthrax vaccine in 2010, there have been slight modifications to 

the licensed indications. In 2015, AVA was licensed for PEP in conjunction with antimicrobials in 

persons who have been potentially exposed to aerosolized B. anthracis spores. In 2018, ACIP 

voted to allow these policy changes. The intramuscular route of administration (IM ROA) may be 

used if the SC ROA presents clinical, operational, or logistical challenges that may delay or 

prevent effective vaccination. In immunocompetent individuals, co-administration of antibiotics 

may be discontinued at 42 days after the first vaccine dose or 2 weeks after the last vaccine 

dose, whichever comes later. Should there be inadequate supplies of AVA available for PEP, 

dose-sparing regimens of either 2 full doses or 3 half doses of AVA may be used to expand 

vaccine coverage.

AV7909, NuThrax®, is an investigational anthrax vaccine under development by Emergent 

BioSolutions in pursuit of licensure with an indication for anthrax PEP. AV7909 is similar in 

composition and manufacturing process to AVA. It consists of the licensed AVA vaccine 

combined with a novel adjuvant, CPG 7909. CPG 7909 is a synthetic immunostimulent 

designed to induce both an enhanced antigen-specific antibody response and a natural killer Tcell immune response when used in combination with vaccines. AV7909 is anticipated to be 

added to the US Government’s Strategic National Stockpile (SNS) starting in July 2019. It is 

also anticipated that AV7909 will replace currently stockpiled AVA for PEP as the stockpiled 

AVA expires. CDC has requested FDA’s permission for emergency use of AV7909 in 

conjunction with appropriate antimicrobial therapy for PEP of anthrax through a Pre-EUA 

submission. The intended use of AV7909 under the proposed EUA is administration as a 2-dose 

series 14 days apart intramuscularly, in conjunction with appropriate antimicrobial therapy in 

adults greater than 18 years of age, including individuals greater than 65 years of age, pregnant 

women, and nursing mothers with suspected or known exposure to B. anthracis. It would be 

used under an IND protocol for those less than 18 years of age.

In terms of the public health importance of this vaccine, while the US government’s anthrax PEP

response plans for a large-scale event include both vaccine and antimicrobials, the currently 

stockpiled quantity of FDA-approved AVA might be insufficient for vaccine coverage in a largescale, aerosolized anthrax attack as previously described. The availability and use of AV7909 

under an EUA would increase the supply of anthrax vaccine and response capability to provide 

vaccine protection should a mass anthrax event occur if the available stockpiled AVA is 

insufficient for the necessary vaccine response. In addition to augmenting vaccine supply to 

enable an effective vaccine response, AV7909 may provide the following additional advantages:

Two intramuscular doses of AV7909 administered 2 weeks apart may provide protective 

immunity 1 or 2 weeks sooner than the licensed 3-dose postexposure prophylaxis regimen 

of AVA. The 2-dose schedule of AV7909 has an operational advantage in a large-scale, 

mass vaccination response and potential for better patient compliance with completion of 

the vaccine dose series in comparison to the licensed 3-dose postexposure prophylaxis 

schedule of AVA.

With fewer injection site-related adverse events (AEs) observed with the IM ROA for AVA 

compared with the SC route, it may be reasonable to anticipate that AV7909 administered 

intramuscularly may have fewer injection site-related AEs compared to AVA given by the SC 

ROA.

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Before presenting the non-clinical data the WG reviewed, Dr. Bower briefly described the 

assays used in these studies. The anti-PA immunoglobulin G (IgG) enzyme-linked 

immunosorbent assay (ELISA) measures the total amount of IgG against PA in micrograms per 

milliliter. It is a species-specific assay, so inter-species measurements may have some 

systematic biases. The toxin neutralization assay (TNA) measures the ability of antibodies to 

neutralize the toxin. It is species-neutral, so measurements between species are comparable.

TNA can be reported in raw or normalized units. The raw unit is effective dilution 50 (ED50), the 

dilution that neutralizes 50% of a fixed amount of toxin. The scale is from ~50 to >10,000. The 

normalized unit is neutralization factor 50 (NF50), which is the ED50 of the sample relative to a 

known reference standard. The reference standard ED50 is ~500, so the scale is smaller, from 

~0.1 to >10.

Inhalation anthrax is very rare, so the effectiveness of AVA cannot be directly assessed for PEP

in humans. For this situation, the FDA has recommended using the Animal Rule where data 

from animals and humans are bridged to determine correlates of protection that can be used to 

predict human survival based on antibody titers generated by the vaccine in humans. AV7909 

was tested in guinea pigs and in non-human primates (NHP). In the guinea pig model, 2 doses 

of AV7909 at days 0 and 14 provided complete protection in all animals, with measurable TNA 

titers when challenged at day 28. The day 70 challenge had one animal with a measurable titer 

that died.

The NHP model was performed the same way. There was only one NHP at the day 28 

challenge with measurable TNA titers that did not survive, and two from the Day 70 challenge 

set. The 70% predicted protection titers for AV7909 are significantly lower than the same 

protection level of 0.56 for AVA. These studies showed that AV7909 is highly protective in 

animal models. The 0.15 NF50 titer level has been proposed by Emergent as the target 

protective level for the Phase II human clinical trial at day 28. Note that the Phase I trials 

achieved levels almost 10-fold higher than this, suggesting that AV7909 should be highly 

protective in humans.

Turning to the clinical immunogenicity studies the WG reviewed, 3 clinical studies have been 

completed as part of the AV7909 development program in which 342 healthy subjects were 

enrolled, 241 of whom were exposed to the combination of AVA + CPG 7909 in various doses 

and immunization schedules. A total of approximately 100 subjects between the ages of 18 and 

50 received one or more doses of the AV7909 formulation currently under development. Dr. 

Bower summarizes the important findings from these studies.

The initial Phase 1a clinical trial assessed the safety and immunogenicity of AVA mixed with 

CPG 7909 in 69 healthy subjects between 18 and 45 years of age. They received either AVA 

alone (0.5 ml), CPG 7909 alone (1 mg in 0.6 ml), or a combination of the two agents (0.6 ml). 

Vaccinations were administered intramuscularly on days 0, 14 ± 1 days, and 28 ± 2 days. The 

geometric mean peak TNA concentration for the AV7909 arm was 8.8-fold higher than that 

observed for the AVA-alone arm. The median time to reach geometric mean of the highest peak 

TNA concentrations for subjects receiving AV7909 was 21 days, a 25-day acceleration over the 

median 46 days it took for the AVA alone arm to reach this concentration. The TNA assay 

results paralleled those observed with anti-PA IgG and both were statistically significant.

The primary objective of the Phase 1b study was to evaluate the safety and tolerability, as 

determined by AE incidence rates, of four AV7909 formulations compared to placebo (saline) 

and AVA alone. Safety and immunogenicity data allowed for the selection of 0.5 ml AVA plus

0.25 mg CPG for use in Phase 2 studies.

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The primary objectives of the Phase 2 study were to assess safety and immunogenicity as 

measured by TNA NF50 values for each study arm at Day 63. The study was designed to 

access both 2 and 3 doses of AV7909 at 2-dose levels in the 5 study arms. Immunogenicity was 

measured on Days 0, 21, 28, 35, 42, 49, 63, 84. The study was designed to look at 

comparability of AV7909 and AVA at day 63, as at the time of this study, AVA was 

recommended in conjunction with antimicrobials for 60 days.

Analysis of the AV7909 TNA threshold of protection data revealed that addition of the CPG 

7909 adjuvant to AVA improved the kinetics and magnitude of the immune response. Two-dose 

AV7909 was found to be comparable to three-dose AVA given IM at Day 63, but achieves peak 

response by day 28 versus day 45 for AVA.

Regarding the clinical safety data, the WG reviewed, during clinical testing in which a total of 

241 subjects in three completed clinical trials were exposed to the combination of AVA + CPG 

7909, systemic reactogenicity manifested primarily as mild to moderate fatigue, muscle ache,

and headache. The most common injection site reactions were mild to moderate pain, 

tenderness, and arm motion limitation. These reactions often resolved within 48 hours after 

dosing. The most common AE reported in ≥ 20% of subjects receiving AV7909 across the three

completed clinical trials were various forms of injection site reaction. AEs associated with CPG 

7909, as reported in a number of reviewed infectious disease vaccine trials, are considered to 

be associated with activation of proinflammatory innate immune responses at the injection site. 

Most reactions are mild to moderate in intensity, of short duration, and remediated with overthe-counter analgesics.

In subjects who received AV7909 as well as with other CPG 7909-adjuvanted infectious disease 

vaccines, the vaccines were generally well-tolerated with a low rate of vaccination 

discontinuation because of AEs. In reviewed trials, rash, positive antinuclear antibody, 

generalized pruritus, urticaria, and fever have been reported as reason for study 

discontinuation. No vaccine-associated deaths or serious adverse events (SAEs) have been 

reported in AV7909 trials or other infectious disease vaccine trials that used CPG 7909. It is 

important to note that these safety studies were all conducted in healthy adults aged 18-50. 

There are no data on the use of this vaccine or other adjuvant CPG 7909 vaccines in children or 

other special populations, including persons greater than 65 years of age.

With regard to the timeline for the BLA submission provided by Emergent BioSolutions 

pertaining to the studies that are underway or planned to start in 2019, non-clinical studies will 

include safety studies in pregnant and juvenile rats. A Phase 2 clinical trial is being conducted to 

assess the safety and immunogenicity of AVA and AV7909 in adults > 65 years of age 

compared to adults 18–50 years of age with preliminary results anticipated in the second or third 

quarter of 2019. Approximately 200 adults aged ≥ 66 years and 100 aged 18 through 50 years 

will be enrolled in the study. The main study goal is to determine optimal dosing for AV7909 in 

the elderly population via the evaluation of three different postexposure vaccine schedules. A 

Phase 2 drug-vaccine interaction study is planned to investigate whether co-administering 

AV7909 with ciprofloxacin or doxycycline affects antibiotic pharmacokinetics or AV7909 

immunogenicity in 210 healthy adults, with results anticipated in 2021. A Phase 3, randomized, 

double-blind clinical trial to evaluate the lot consistency, immunogenicity, and safety of a 2-dose 

AV7909 series administered intramuscularly at Day 0 and 14 in 3850 healthy adult subjects is 

planned to start in 2019. It is anticipated that this WG will reconvene in 2021 to review these 

data.

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❑

❑

❑

❑

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With respect to the WG’s discussions, the WG felt that the data show that AV7909 generates a 

similar to better immune response when compared to AVA given by the IM route of

administration over the time points reviewed and would provide similar protection after exposure 

to aerosolized B. anthracis spores. The data suggest that two doses two weeks apart produce a 

rapid response providing the highest level of protection early, while two doses four weeks apart 

provide a higher sustained response. However, limited safety data are available. Therefore, until 

there are more data available, the WG was not in favor of a preferential use of AV7909 over 

AVA. Given the high mortality associated with inhalation anthrax, the WG felt that the benefits of 

providing prophylactic vaccine outweighed the potential risk of AV7909. The WG supported the 

use of AV7909 if supplies of AVA are exhausted or unavailable once the pre-EUA package has 

been accepted by FDA. The WG also was concerned that there are no safety data in children or 

other special populations. However, given the high mortality associated with anthrax, the WG 

felt that the benefits of the vaccine outweighs the potential AEs in these populations and would 

be an option for PEP if AVA supplies are exhausted or unavailable once pre-EUA package has 

been accepted by FDA.

The proposed wording for the MMWR Policy Update is:

AV7909 is scheduled to become part of the US government’s Strategic National 

Stockpile by July 2019 and is currently under consideration for use under an Emergency 

Use Authorization protocol.

AVA is preferred for PEP for potential exposure to aerosolized B. anthracis spores as it 

is licensed for this indication. Additional safety data will be reviewed by ACIP as they 

become available, and recommendations on preferential use will be updated as needed.

However, based on very limited safety and immunogenicity phase 2 data, AV7909 

appears safe and elicits a robust immune response in healthy adults. 

AV7909 could be an option for PEP if AVA is not available. As with AVA, antimicrobials 

should be taken for up to 60 days in conjunction with the vaccine

CDC guidance for AV7909 will include statements on dosing schedules and special 

populations

Discussion Points

Dr. Walter requested clarity regarding whether both AV7909 and AVA have the same amount of 

antigen and are made by the same manufacturer, as well as clarity on how the SNS works and 

would increase the supply.

Dr. Bower replied that AV7909 and AVA have the same amount of antigen and are made by the 

same manufacturer. He indicated that there is set amount of AVA in the SNS, but it is expiring 

and there is no plan to purchase more AVA. Therefore, AV7909 will be coming into the SNS. 

Over time, the balance will shift from more AVA to more AV7909. The hope is that by that time, 

there are more data such that ACIP can make a preferential decision on its use.

Dr. Cohn emphasized that the purpose of this presentation and the information being included in 

the updated recommendations was to ensure that states use this recommendation and report 

for their planning, so CDC wants them to have information available. However, in the event of a 

widespread release and a need to use this product prior to the product being licensed, an 

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emergency ACIP meeting would be convened and a vote would be taken at that time for use of 

this vaccine.

Dr. Frey suggested that it might be helpful for the group to understand that the AVA in the SNS 

is an older vaccine.

Dr. Bower indicated that AVA has expiration dates and is on an expiration date extension 

program, but the thought is that CDC wants to move away from that. Based on the logistical 

advantages of AV7909, they want to move toward that because it is anticipated to provide better 

protection by giving the vaccine over a shorter period of time and the adjuvant boosting the 

response.

Dr. Walter asked whether AVA still being manufactured.

Dr. Bower responded that Emergent BioSolutions has the capacity to make AVA and it is still 

going to be made for PrEP.

Dr. Szilagyi requested clarification regarding the concept of the AVA stockpile being exhausted 

this meant in the US or if there is a worldwide distribution plan and any agreements with other 

nations or stockpiles.

Dr. Bower indicated that the SNS belongs to the US government, and AV7909 is not intended to 

be used by anybody but the US government. He was not privy to information about any 

agreements with other nations/stockpiles.

Dr. Lee wondered whether the WG would consider age-specific recommendations as data start 

emerging, and whether the recommendation would differ for pregnant women and children 

versus the adult population. She was thinking about understanding the risk-benefit in those 

populations given what is currently known, understanding that this information probably will 

change over time.

Dr. Atmar added that it was unclear whether data would be available in pediatric or other special 

populations. The Institute of Medicine (IOM) has concluded that it would be reasonable to 

conduct studies in pediatric patients, but he did not know whether any were planned. There are 

still ethical considerations that must be addressed in such discussions.

Dr. Bower thought perhaps it would be administered under an IND as is done with AVA if a 

situation arises in which there is a need to use AV7909.

It seemed to Dr. Lee that in a PEP setting, the benefit-risk would be highly in favor the benefit of 

giving it in the absence of additional data. She was thinking about the overall supply and the 

balance of that supply over time. If there is availability of AVA alone, that might be reasonable to 

consider.

Dr. Frey indicated that there might be some CPG data available in pediatric populations for 

different vaccines. This was a controversial adjuvant in its earlier days, but many studies since 

that time have shown it to be effective and thus far safe. An example of Dr. Lee’s point is that 

smallpox would be given to children and pregnant women if it was thought to be emergent.

Dr. Cohn added that CDC has protocols in place to perform a substantial amount of data 

collection on implementation among children in the event of an incident.

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To follow up on the CPG comment, Dr. Stephens said he believed this to be a new CPG that 

has not been used extensively in other vaccines.

Dr. Bower confirmed that there are no licensed vaccines that use this particular adjuvant. 

However, there have been trials in malaria vaccine and hepatitis B vaccine that use this 

adjuvant. The WG reviewed those studies and they did not give any signal to indicate that there 

was anything more than some mild to moderate AEs and no SAEs. He did not know the status 

of those vaccines.

Sean Bennett (Emergent BioSolutions) confirmed that CBG 7909 was evaluated in previous 

investigational vaccine trials. As far as he knew, none of those have continued development. 

There are some limited pediatric safety data from HEPLISAV-B

®

that uses the 1018 

immunostimulatory sequences (1018-ISS), which is a similar mechanism of action. 

Next Generation Anthrax Vaccine: AV7909

William Bower, MD, FIDSA

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention

Dr. Bower next presented on the WG’s AVA PrEP booster dose interval discussions, indicating 

that it was important to note for this discussion that AVA is approved for PrEP in persons at high 

risk of exposure to B. anthracis, such laboratory workers handling B. anthracis or veterinarians 

working with potentially infected animals. The policy question ACIP was asking during this 

session was related to persons not at high risk, but who may in the future be at high risk of 

exposure. Thus the policy question is, “Can persons who are not at current high risk of exposure 

to B. anthracis spores maintain adequate immunity by being boosted with AVA every three

years after immunological priming, with the caveat that if they were required to enter a high-risk 

area, they would receive a booster with or without antimicrobials, depending on the timing of 

their last booster dose?” The population of interest is persons aged 18 years or older with 

potential future, but not current, exposure to aerosolized B. anthracis spores. The intervention is 

a 6-month priming schedule at 0, 1, and 6 months followed by a booster every three years with 

AVA and compared to the currently licensed AVA PrEP vaccine schedule. The outcome of 

interest is protection. Before presenting the data to support the policy change for this vaccine, 

Dr. Bower provided some background information important for understanding the PrEP anthrax 

vaccine recommendations. He emphasized that while he already provided a description of AVA

(BioThrax®), this presentation would focus on the vaccine schedule for PrEP rather than PEP as 

in the last presentation.

AVA is licensed for PrEP of anthrax in persons 18 to 65 years of age at high risk of exposure 

and is given by the IM route as a 6-month priming series at 0, 1, and 6 months, with booster 

doses given at 12 and 18 months and annually thereafter. This vaccine is quite old, with a long 

history. In the 1950s, the vaccine was made at Ft. Detrick from a cell culture filtrate and 

precipitated with alum. This is the “Wright” or “Ft. Detrick” formulation which was studied 

extensively by Dr. Phil Brachman for prevention of anthrax in textile mill workers exposed to 

animal hides contaminated with B. anthracis spores. In the 1960s, the manufacturing process 

was improved, resulting in increased PA concentration, purity, and potency. This new 

formulation was referred to as the “Lansing” formulation and was produced by the Michigan 

Department of Health and Human Services (MDHHS) in Lansing, Michigan. In the 1970s, the 

“Lansing” formulation was licensed using data from the Brachman studies. In 2008, the twoThis document has been archived for historical purposes. (3/1/2019) 

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week priming dose was dropped and the ROA was changed from SC to IM for PrEP. In 2012 

and subsequent to the last ACIP review, the priming series was changed from 5 doses to 3

doses at 0, 1, and 6 months with the last 2 priming doses changed to booster doses at 12 and 

18 months and an annual booster thereafter. This enabled laboratory work or deployment to 

high risk areas to occur after 6 months rather than 18 months under the old priming schedule.

AVA was last reviewed by ACIP in 2009 and recommendations were published in 2010. ACIP 

did not recommend that emergency responders routinely receive anthrax PrEP, but did suggest 

that emergency responders on a voluntary basis could opt-in to receiving PrEP. They also noted 

that the data suggested an increased booster interval does not decrease the ultimate immune 

response.

As discussed previously, B. anthracis is considered one of the most likely pathogens to be used 

as a bioweapon. As illustrated earlier with the image of a hypothetical wide area outdoor 

release, modeling scenarios show how a large release of B. anthracis spores from a commuter 

train traveling through a densely populated area could theoretically expose tens to hundreds of 

thousands of persons to anthrax resulting in a public health emergency. If this type of event 

were to occur, having a group of emergency responders with a primed immune response and 

only requiring a booster dose to begin work in the affected area would greatly improve the surge 

capacity for the public health response.

In terms of the public health importance of this policy question, AVA for PrEP is only indicated 

for persons currently at high risk of exposure to anthrax. However, there are groups of persons, 

such as the military, who may need to enter an area of high risk, then leave, and may not return 

for several years. There also are persons, such as emergency responders, who are not at 

current risk, but might be required to enter an area of high risk on short notice. New data on 

immunogenicity following extended booster intervals suggest that in these situations, persons 

can have a booster interval of greater than one year and maintain a robust amnestic response 

to a booster dose. This potentially would reduce the number of AEs by decreasing the number 

of vaccinations and decrease logistic issues related to deploying emergency responders should

a mass anthrax event occur. If approved, an updated policy statement will be published that will 

combine information from the previous 2010 MMWR document with updated indications and 

dosing schedules for AVA.

With regard to the studies that provide the basis for an extended booster dose interval, the main 

concern with extending the booster interval is the level of protection at the pre-boost time points 

when antibody levels are at their lowest. The correlates of protection approach was designed to 

evaluate protection at those time points, which should be the minimum protective levels for each 

schedule. Since inhalation anthrax is very rare in humans, the effectiveness of AVA cannot be 

directly assessed for PrEP. Instead, the correlates of protection model must be used to estimate 

human survival at vaccine-generated anti-PA IgG concentrations compared to NHP anti-PA IgG 

concentrations and survival data.

The animal antibody concentration and survival data came from the 2012 Quinn study in which 

NHP were given AVA at full strength or at various dilutions at 0, 1, and 6 months to generate a 

range of anti-PA IgG concentrations. The animals were then challenged with 200-400 LD50 B.

anthracis spore concentrations at 12, 30, and 52 months. The antibody concentrations and 

survival data were placed in a logistic regression model to generate a survival curve. This study 

showed that three IM priming doses elicited sustained production of functional PA-specific 

interferon gamma- and interleukin-4-secreting T-cells, lymphocyte proliferation responses, and 

memory B-cells for the study duration. In 2014, Chen et al. performed a comprehensive analysis 

of 21 humoral and cell-mediated NHP immune-response variables at multiple time points. The 

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anti-PA IgG level at the last available time point before challenge and lymphocyte stimulation 

index at study months 2 and 6 were identified consistently as COP. Anti-PA IgG levels and 

anthrax lethal toxin neutralization activity at both the time of exposure and month 7 were 

practicable and accurate metrics for correlating vaccine-induced immunity with protection 

against inhalation anthrax. The model indicated that even very low levels of circulating antibody 

at the time of challenge correlated with significant levels of protection.

All vaccinated NHP had measurable antibodies at month 7. By time of challenge, some of the 

1:10 and lower dilution groups no longer had measurable serum anti-PA IgG levels and some of 

the animals with undetectable antibody levels still survived. Fisher’s exact test was used to 

compare the overall survival rates between all pairs of challenge times for the vaccinated NHP. 

There was a statistically significant difference between the survival of animals challenged at 12 

months and that of animals challenged at 30 months; however, no statistical differences were 

evident between animals challenged at 12 months and 52 months or between animals 

challenged at 30 months and 52 months. The Quinn study showed that the 3-dose priming 

series at 0, 1, and 6 months with a human dose and dilutions of up to 1:10 of AVA provided 

levels of protection from 60% to 100% against inhalation anthrax for up to 4 years in NHP. In 

general, serum anti-PA IgG and TNA responses remained significantly above control levels 

through 50 months, which was the last time point measured. It also showed that protection was 

achieved even when using diluted vaccine doses.

The human data come from one main source. The 2014 Wright paper looked at the licensed 

priming series and increasing booster dose intervals that provided the immunogenicity data for 

the correlates of protection model. Data from the 2013 and 2014 Pittman papers support the 

robust amnestic immune response seen in the Wright study. This table shows the different arms 

and number of arm participants used to assess the booster dose intervals in the Wright study:

The 7-IM arm represents the current licensed PrEP schedule as the 2-week dose was dropped 

from the schedule in 2008. The 4-IM arm represents the proposed PrEP schedule with an up to 

3-year booster interval.

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In the Wright study, all groups produced high immune responses by month 7 and there were no 

statistically significant differences between groups at that time point. Only 2 out of 1303 

vaccinated participants did not produce detectable antibody at month 7. Both individuals 

dropped out of the study before receiving another dose, so there are no data on follow-up. All 

groups and all remaining participants responded to boost. The 5-IM and 4-IM groups showed

gradually receding levels of antibody in the periods between boosts relative to the 7-IM 

schedule. Geometric mean antibody levels remain well above background through month 42 in 

all groups. At month 42, all of the 7-IM cohort had detectable antibodies, 97.9% of the 5-IM 

group had detectable antibodies, and 80.2% of the 4-IM group had detectable antibodies 

significantly higher than controls. Response to the month 42 boost in the 4-IM group was nearly 

double that of the 7-IM group and statistically significantly superior. The 5-IM group was also 

higher than the 7-IM group, but not statistically significant.

The aim of the 2014 Pittman study was to compare the level of persistence of the anti-PA IgG 

concentrations and toxin neutralization response in persons who had a delay of up to 7 years in 

receipt of the 6-month dose compared to those who received the dose on schedule. The 

delayed cohort in the Pittman study was non-inferior to the on-schedule cohort for both anti-PA 

IgG and TNA ED50 at day 28 and 180 post-vaccination. In fact, the delayed cohort was superior 

to the on-schedule cohort on days 28 and 180 for both mean anti-PA IgG concentration and 

mean TNA ED50 titer. Furthermore, antibody levels receded significantly faster in the onschedule cohort than in the delayed group, thus demonstrating a reason to delay the booster 

dose.

In summary, the data presented confirm that a 3-dose IM priming series administered at 0, 1,

and 6 months followed by boosters at 18 and 42 months or a single booster at month 42 

established robust immunological priming and sustained immunological memory. The correlates 

of protection model predicts high survival estimates with even the most reduced boosting 

schedule. As expected, an increasing period between booster doses resulted in lower levels of 

anti-PA IgG just prior to vaccination. However, the persistence of quantifiable anti-PA IgG and 

the exceptional recall responses to a booster dose administered at either month 18 or 42 were 

noteworthy. The greater interval between boosters generated a significantly higher response, 

which if assuming a similar decay curve, should provide higher protection between booster 

doses. Increasing the intervals between booster doses should decrease the frequency of 

vaccine related AEs and decrease the operational cost of administering the vaccine. These 

data, together with duration of protection studies in NHP, suggest that AVA established longterm antibody secreting plasma cell populations and robust immunological memory manifested 

by rapid and high anamnestic responses.

With respect to the WG discussions, the WG discussed a 3-year booster interval for persons at 

current high risk of exposure to B. anthracis. The WG felt for persons at continuous high risk of 

exposure that the higher titers just prior to boosting were the most important factor when 

deciding the booster interval. This is provided by an annual booster and thus the WG was not in 

favor of extending the booster interval to greater than one year for individuals at current high 

risk of exposure. However, in persons not currently at high risk of exposure, but who may in the 

future be at high risk of exposure, the WG felt the data showed that a booster interval of up to 3 

years provides a robust amnestic immune response. There are also limited data suggesting the 

booster interval could be up to 5 to 7 years, but more data are required to make a 

recommendation for greater than 3 years at this time.

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The work group also felt a gap in recommendations should be addressed for persons who are in 

the process of receiving the 6-month priming series and are required to enter a high-risk area 

prior to completing the priming series. These recommendations came from review of the data on 

immune response to the AVA PrEP priming series that show 3 doses provide priming for an 

amnestic immune response and from the AVA PrEP data that show 3 doses given 2 weeks 

apart provides high levels of protection. There are no data on the effect on the immune 

response for starting PrEP by the IM route and switching to the SC route to join the PrEP

schedule; however, there is no reason to believe that the immune response would be adversely 

affected by mixing the route of administration. While in the high-risk area, the licensed booster 

schedule for high risk exposure would apply.

In terms of the recommendation, AVA is licensed for prevention of anthrax in persons at high 

risk of exposure to Bacillus anthracis. There are no proposed changes to this indication. The 

WG is proposing a booster interval for AVA that is longer than the licensed booster schedule for 

persons who are not currently at high risk of exposure, but who may need to deploy to a highrisk area quickly. While in the high-risk area, the licensed booster schedule for high risk 

exposure would apply. The proposed wording for the MMWR Policy Update for 

recommendations on priming persons not currently at high risk of exposure to anthrax is:

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For persons who lack current, but may have future, high risk of exposure to B. anthracis, 

AVA may be given as an intramuscular 3-dose priming series at 0, 1, and 6 months, 

followed by an intramuscular booster every 3 years.

After receiving the 3-dose priming series, persons who have not received a booster dose 

in the last 6 months but need to enter an area where B. anthracis is suspected to be in 

use would be given an IM booster dose and either:

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Wait 2 weeks to enter the high risk area 

OR 

If required to enter immediately, take antimicrobial PrEP for 2 weeks

Persons who have not completed the priming series for PrEP with AVA who are exposed to 

aerosolized B. anthracis spores should join the PEP schedule. This table provides information 

on additional AVA doses needed based on the number of PrEP doses already received and 

recommended antimicrobial coverage:

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Dr. Bower presented for discussion and a motion the following policy change that ACIP would

be asked to vote on later in the day:

“To maintain memory response, a booster dose of AVA should be given every 3 years to 

persons who received an AVA priming series if they lack current high-risk exposure to B. 

anthracis.”

Discussion Points

Dr. Atmar said that to be clear, already there is a recommendation for off-label use of the 

vaccine for groups who are worried about potential future exposure, such as emergency 

responders. This is providing clarification of how often one can boost those individuals to try to 

maintain some immune memory. Thus, it is an off-label recommendation for an already off-label 

use of the vaccine.

Dr. Cohn added that this is a group that is not recommended to receive the vaccine, but there is 

permissible language with regard to using the vaccine.

Dr. Bower indicated that the 2010 recommendation said they could voluntarily receive the 

vaccine, but they want to provide some guidance about how to go about it. The WG thinks that 

this would be a better use than trying to get the vaccine annually.

Dr. Moore acknowledged that there are not sufficient data available currently on the sustaining 

of titers following booster doses and the opportunity to space boosters out for those at ongoing 

high risk, but wondered if the WG would consider this should additional data become available 

to reassure them that an interval greater than one year would be appropriate for these 

individuals.

Dr. Bower responded that the FDA has seen the data and did not want to extend the booster 

dose for people at current high risk. The Department of Defense (DoD) will have some 

opportunities to assess that question, so if promising data come up, the WG will certainly 

present it.

Dr. Atmar pointed out that the Wright study looked at intervals of 2 and 3 years and suggested 

that an interval longer than 1 year led to a proportion of persons on the longer interval being 

potentially susceptible. That was considered to be an undue risk for individuals who have 

continued exposure, so it is unlikely based on the Wright data with AVA that such data would 

come forward in the future. Certainly, if they were generated the WG would likely reconsider it, 

but there already are some pretty good data suggesting that is not likely to be the case.

Dr. Moore said that she was thinking about it looking like there was a really nice response after 

that first annual booster dose and a slower degradation. While she understood that it was not an 

issue for discussion currently, she wondered what it would take to get there.

Dr. Lee observed that it seemed that moving away from a more permission recommendation to 

a routine recommendation would be helpful because it would result in better workforce 

readiness to respond to events, and wondered whether that was part of the intent with this 

revised recommendation.

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Dr. Bower replied that first responders in high target areas probably would take advantage of 

this, and spreading out the booster dose interval would make it more appealing to them. As 

AVA expires and leaves the stockpile, there has been some consideration of making it available 

to first responders so that they could be prepared for an event. This is why they are seeking 

some guidance on how that might occur.

Dr. Atmar added that the recommendation is still permissive. The booster dose is permissive for 

off-label use of the vaccine, but the way it is stated it says for those who want “to maintain 

immune memory.” This would give access to the vaccine for groups like emergency responders 

who want to take advantage of access to the expiring vaccine. 

Dr. O’Neal Eckert (ACOG) wondered whether any pregnant or post-partum breastfeeding 

women would be in the booster studies after the priming.

Dr. Bower indicated that currently, consideration is being given to collaboration with the DoD 

which does have women who are inadvertently vaccinated during pregnancy.

Dr. Cohn clarified that the permission language regarding people who are not at increased risk 

is for persons 18 years of age and older.

Dr. Baker (IDSA) observed that “should be given” did not sound very permissive in these 

presumable low-risk individuals.

Dr. Atmar replied that the qualifier “to maintain memory response” it should be given. It is not 

saying that the booster has to be given. 

Dr. Cohn clarified that when this language is published in the full recommendation and report, it 

would be language below the language around use of this vaccine in persons not at high-risk, 

which is permissive language.

Dr. Stephens emphasized that these individuals already have been vaccinated, so there must 

have been some anticipation about risk. This is simply extending the booster to a longer 

interval. He was concerned about the word “maintain” when it is actually about eliciting a 

memory response, not necessarily maintaining it. The memory response is already there. He 

recommended that the word be changed from “maintain” to “elicit.” Dr. Gravenstein suggested 

stating, “To boost memory response.”

Dr. Hunter shared Dr. Baker’s concern about “should.” He had a feeling that this could be 

excerpted and people could leave out part of this when they copy it to their friends and 

colleagues. Therefore, he suggested replacing “should” with “may.”

Dr. Stephens moved to accept the recommendation as stated. Dr. Lee seconded the motion.

Dr. Cohn stressed that minor language modifications could be made at the time of the vote that 

do not change the intent of the motion, but are helpful for clarification purposes.

Dr. Romero indicated that the language would be modified before being presented for the vote 

later in the afternoon.

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In the afternoon following the public comment period, the discussion and vote on the anthrax 

policy change continued. Dr. Bower read the following slightly edited language into the record 

for final discussion and the vote:

“Among persons not currently at high risk of exposure to B. anthracis who have been 

previously primed with AVA and wish to maintain protection, a booster dose of AVA 

should be given every 3 years.”

Dr. Atmar recalled the desire in the earlier discussion to change “should” to “may.”

Dr. Szilagyi clarified that the WG added the clause at the beginning “among persons not 

currently at high risk of exposure and who wish to maintain protection” and thought it actually 

would be more precise to say “should.” It does not imply that all people “should.” This is just 

among the subgroup.

Dr. Hunter reiterated his concern that the statement could be excerpted and should, therefore, 

be “may.” 

Dr. Atmar agreed that “should” could be misinterpreted by some end-users, while “may” offers 

the same idea without the push.

Dr. Bernstein suggested keeping “should” and changing “given” to “considered.”

Dr. Lee asked whether, if they used “may” and then someone went 6 years whether they would 

have to restart their primary series. Her concern was that if the interval was too long, they would

lose the benefit of having the primary series and the booster would not be sufficient.

Dr. Bower indicated that they would never have to restart the primary series.

Dr. Atmar recalled that one of the points made during presentation was there are some data that 

suggest the interval can be even longer. Those data will be further developed and probably will 

be reconsidered in a few years when they are available. The 3-year interval is what there are 

data for currently as an acceptable minimum interval for those not at continuous risk. The 

“should” has been suggested to be used where there is the thought that the person should be 

getting it and not as a permissive suggestion. That said, Dr. Szilagyi agreed that it would be fine 

to use “may.”

Dr. Frey recalled that in the earlier discussion, it was suggested that language stating “to 

maintain or boost memory response” needed the word “should” because that is what there are 

data for.

Dr. Bernstein suggested, “A booster dose of AVA should be given every 3 years to maintain 

protection.”

Atmar suggested, “A booster of AVA may be given every 3 years among persons not currently 

at high risk of exposure to B. anthracis who previously have been primed with AVA and wish to 

maintain protection.” By flipping the statement Dr. Bower just read, the idea would be captured 

and it would be made clear that it is still permissive as opposed to mandated.

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For the sake of accuracy, Dr. Baker (IDSA) suggested that the desired words be displayed 

before the vote.

 

Dr. Atmar suggested the following revised proposed recommendation language into the record, 

which was displayed for the vote: 

“A booster dose of AVA may be given every 3 years to persons not currently at high risk 

of exposure to B. anthracis who have been previously primed with AVA and wish to 

maintain protection.”

Dr. Cohn clarified that they must first motion/second to vote on the revised language, and then 

motion/vote on approving the recommendation as revised.

Dr. Atmar made a motion to approve the recommendation as proposed, which Dr. Gravenstein 

seconded.

Motion/Vote #1: To Accept the Revised Language for the Vote on Anthrax 

Vaccine Use for PrEP in Persons NOT at Current High Risk of Exposure to Anthrax

Dr. Atmar made a motion to approve for a vote the revised the recommendation language as 

last proposed reading, “A booster dose of AVA may be given every 3 years to persons not 

currently at high risk of exposure to B. anthracis who have been previously primed with AVA 

and wish to maintain protection.” Dr. Gravenstein seconded the motion. The motion carried with 

15 affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

15 Favored: Atmar, Ault, Bernstein, Ezeanolue, Gravenstein, Frey, Hunter, Lee, McNally, 

Moore, Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Motion/Vote #2: Anthrax Vaccine Use for PrEP in 

Persons NOT at Current High Risk of Exposure to Anthrax

Dr. Atmar made a motion to approve the revised policy change recommendation reading, “A 

booster dose of AVA may be given every 3 years to persons not currently at high risk of 

exposure to B. anthracis who have been previously primed with AVA and wish to maintain 

protection.” Dr. Gravenstein seconded the motion. The motion carried with 15 affirmative votes, 

0 negative votes, and 0 abstentions. The disposition of the vote was as follows:

15 Favored: Atmar, Ault, Bernstein, Ezeanolue, Gravenstein, Frey, Hunter, Lee, McNally, 

Moore, Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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Introduction

Emmanuel (Chip) Walter, MD, MPH 

Chair, Influenza Work Group

Dr. Walter reminded everyone that during the October 2019, there were presentations on: 1) the 

Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) study of effectiveness of 

influenza vaccine in preventing hospitalization among pregnant women; and 2) a study of 

Fluzone® Quadrivalent at a 0.5mL dose for children aged 6 through 35 months, which was 

approved by the FDA in January 2019.

Since the October 2018 ACIP meeting, the WG has engaged in several meetings and calls 

during which members heard presentations on: 1) 2018-2019 season US influenza activity; 2) 

interim 2018-2019 season vaccine effectiveness (VE) estimates from the US Flu VE Network; 

and 3) results of the third Vaccine Safety Datalink (VSD) study of inactivated influenza vaccines 

(IIVs) and spontaneous abortion (SAB) among pregnant women. The third VSD study was a 

follow-up to an earlier study presented to ACIP in October 2017, which detected an association 

between receipt of IIV and SAB in first 28 days post-vaccination when an H1N1pdm09-

containing vaccine had also been received during the previous season.

The agenda for this session included the following topics:

2018-2019 US Surveillance Update

Interim Estimates of 2018-2019 Seasonal Influenza VE: US Flu VE Network

Phase III Randomized Observer-Blind Comparator-Controlled Study of Afluria® Quadrivalent 

(Afluria® QIV) for Children 6 through 59 Months

Case-Control Study of IIV and SAB in the VSD 2012-2013, 2013-2014, and 2014-2015

Summary and WG Considerations

Influenza Surveillance Update

Lynnette Brammer, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Brammer presented an update on the US influenza activity for the current season, provided 

preliminary in-season burden estimates for influenza, additional information on virus 

characteristics for the currently circulating viruses, and an update on vaccine virus component 

selection for the 2019-2020 influenza season.

In terms of the week ending February 16, 2019, MMWR Week 7, based on information reported 

to CDC by US clinical laboratories, 27% of tests were positive. This has been a very strongly 

predominant influenza A season. Based on data from public health laboratories across the 

country, the predominant influenza A virus was A(H1N1)PDM09. Those represented 

approximately 75% of the influenza A viruses for the season overall. However, in recent weeks, 

influenza A(H3N2) viruses have increased and for the most recent week represented 47% of the 

Influenza

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influenza viruses detected. There has been very little influenza B activity. One of the unusual 

aspects of this seasons is that while there has been H1 predominance nationally, there have 

been regional differences. H3N2 has been the predominant virus in the Southeast for the entire 

season. In the most recent 3 weeks in 3 other regions, the number of H3 viruses have been 

either equal to or greater than the number of H1 viruses.

The percent of outpatient visits for influenza-like illness (ILI) also continues to increase. In the 

most recent week, 5.1% of visits to outpatient clinics were for ILI. This is higher than in several 

recent seasons, but is still well below what was observed last year. For the most recent week, 

New York City (NYC) and 30 states had high levels of ILI. An additional 11 states and the 

District of Columbia (DC) had moderate activity.

While the overall rate of laboratory-confirmed influenza-associated hospitalizations was 

27.4/100,000 population, the highest rate is among those 65 years of age and older, followed by 

children 0 through 4 years of age. At this time, this season is fairly average and is well below 

what was observed last year.

The percent of influenza and pneumonia deaths reported to the National Center for Health 

Statistics (NCHS) has exceeded the epidemic threshold for only two weeks thus far. The highest 

level was 7.4%, which is well below what was seen last year at peak of 10.8%. Even though 

pneumonia and influenza mortality has been relatively low this season, there have been 41 

influenza-associated pediatric deaths. Among those 41 deaths, all but 2 were influenza A 

viruses. The majority of the influenza A viruses from those children that have been subtyped 

have been H1N1 as would be expected.

This year for the 2018-2019 season, CDC published preliminary in-season burden estimates for 

the first time. These estimates show that for this season so far, there have been up to 20.4 

million influenza illnesses, up to 9.6 million medical visits, up to 256,000 influenza-associated 

hospitalizations, and up to 22,300 influenza-associated deaths. To put that into context, since 

the influenza pandemic in 2009, the range of deaths was 12,000 to 79,000 last year. Granted 

these are in-season deaths, the estimate is preliminary, and the season is not over yet. It can 

basically be said that the estimate is now higher than what was seen in the very low 2011-2012 

season, but still well below what was seen last year [www.cdc.gov/flu].

In terms of the characteristics of currently circulating influenza A (H1N1)pdm09 viruses collected 

from September 30, 2018 to present, all 626 influenza A (H1N1)pdm09 viruses from the US

tested so far belong to the single genetic group 6B.1. However, a considerable amount of

genetic diversity has emerged within clade 6B.1. Of the 263 (H1N1)pdm09 viruses that have 

been antigenically characterized using a hemagglutination inhibition (HI) assay with ferret 

antisera, 259 (98.5%) were similar to both the egg and cell culture-propagated 

A/Michigan/45/2015 reference virus. However, testing with human sera recently has shown 

reduction in some of the titers against some recent influenza A (H1N1)pdm09 viruses compared 

to titers against A/Michigan/45/2015.

Phylogenetic analysis of the HA genes of recent H3N2 viruses show extensive genetic diversity 

in multiple genetic clades and subclades co-circulating. The 3 predominant clades or subclades 

are the 3C.2a1, which is the clade to which the current vaccine strain belongs, 3C.2a, and 

3C.3a. The proportion and geographic spread of viruses belonging to clade 3C.3a clade has 

increased in recent weeks. The most recent figure was that for the season, they represent 52% 

of the H3N2 viruses circulating. Of the 194 A(H3N2) viruses antigenically characterized by focus 

reduction assay (FRA), 128 (66%) were well-inhibited by ferret antisera raised against the

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A/Singapore/INFIMH-16-0019/2016 (3C.2a1) cell-propagated reference virus. Among the 66 

viruses that reacted poorly against the A/Singapore, 65 (98.5%) belonged to clade 3C.3a.

There are currently 3 genetic groups of B/Victoria lineage viruses co-circulating. The V1A group 

was the older Brisbane-like vaccine strain clade. The V1A.1 clade is the clade to which the 

current B/Colorado virus belongs and was referred to last year as V1A-2DEL because it has a 

2-amino acid deletion in the hemagglutinin. The V1A-3DEL subclade has 3 amino acid deletions 

in the hemagglutinin. Of the 40 B/Victoria lineage viruses antigenically characterized, 33 

(82.5%) were similar to the cell-propagated B/Colorado/06/2017-like V1A.1 reference virus that 

is in the vaccine. All 7 viruses that reacted poorly to A/Colorado belonged to the V1A group, 

which is the older group similar to the old B/Brisbane vaccine strain.

All of the B/Yamagata lineage viruses tested belong to a single genetic group, Y3. All influenza 

B/Yamagata-lineage viruses antigenically characterized are similar to cell-propagated 

B/Phuket/3073/2013 (Y3), the reference vaccine virus representing the influenza B/Yamagatalineage component of the 2018-2019 Northern Hemisphere quadrivalent vaccines.

WHO held its Consultation on the Composition of Influenza Virus Vaccines for Use in the 2019-

2020 Northern Hemisphere Influenza Season on February 18-21, 2019. Their recommendation 

was to maintain both of the influenza B components, B/Colorado/06/2017-like virus 

(B/Victoria/2/87 lineage) and B/Phuket/3073/2013-like virus (B/Yamagata/16/88 lineage), which 

will be only in quadrivalent formulations. They recommended updating the (H1N1)pdm09 

component to an A/Brisbane/02/2018 (H1N1)pdm09-like virus. WHO elected to delay the 

decision on the A(H3N2) virus component until March 21, 2019 to allow time for collection of 

more data and to allow for completion of testing on potential vaccine candidate viruses. FDA’s 

VRBPAC will meet on March 6, 2019 and is also expected to delay this decision.

In summary, influenza activity remains elevated. Influenza A(H1N1)pdm09 viruses have 

predominated overall, but H3N2 viruses were detected more commonly than H1N1 viruses in 

the Southeast and have increased in other regions in recent weeks. An increasing proportion of 

the H3N2 viruses belong to the 3C.3a genetic group, which is antigenically distinct from the 

3C.2a genetic group. WHO’s recommendation for the H3N2 component for the 2019-2020 

Northern Hemisphere vaccine has been delayed until March 21, 2019 to allow for the collection 

of more data and to allow for completion of testing of potential candidate vaccine viruses.

Interim Estimates of 2018–19 Seasonal Influenza Vaccine Effectiveness 

Against Medically Attended Influenza from the US Flu VE Network

Brendan Flannery, PhD

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Flannery presented data from the US Flu VE Network. Participating since the 2012 influenza 

season, the 5 sites and their Principal Investigators (PIs) are:

Baylor Scott and White Health: Manju Gaglani

Kaiser Permanente Washington: Mike Jackson, Lisa Jackson

Marshfield Clinic Research Institute (Ed Belongia, Huong McLean)

University of Michigan (Arnold Monto, Emily Martin)

University of Pittsburgh (Rick Zimmerman, Tricia Nowalk)

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As a reminder, the US Flu VE Network enrollees include outpatients aged >6 months with 

acute respiratory illness with cough ≤7 days duration. For this enrollment period, sites began 

enrollment once there was influenza activity at their sites. The period of influenza positivity 

ranged from November 23, 2018–February 2, 2019. A test-negative design was utilized for this 

analysis, which compares the vaccination odds among influenza reverse transcriptase 

polymerase chain reaction (RT-PCR) positive cases and RT-PCR negative controls. The 

vaccination status for these interim analyses was receipt of at least one dose of any 2018-2019

seasonal influenza vaccine according to medical records, immunization registries, and/or selfreport. One site uses medical records and immunization registries only, and four sites also use 

self-reports for interim estimates. Adjustments in this analysis included study site, age, selfrated general health status, race/Hispanic ethnicity, interval from onset to enrollment, and 

calendar time. The interim estimates that were published on February 15, 2019 in the MMWR

included 3254 subjects enrolled from November 23, 2018-February 2, 2019 at the 5 sites. Of 

these, 465 (14%) were influenza RT-PCR positive and 2789 (86%) tested influenza RT-PCR 

negative. Among the influenza positives, 63% were H1N1, 22% were H3N2, 13% were 

unsubtyped A, 1% were B/Yamagata, and 1% were B/Victoria [Doyle et al, MMWR 2019].

At the time of the interim report, approximately 20% of enrollees were testing positive. 

Considering any influenza A or B virus for all age groups, 43% of influenza positives were 

vaccinated and 57% of influenza negatives were vaccinated, for an adjusted VE of 47% (CI: 34, 

57). By age group, VE was 61% (CI: 44, 73) for children 6 months through 17 years of age, 37% 

(CI: 9, 56) for adults 18 through 49 years of age, and 24% for adults ≥50 years of age. The 

confidence interval for the ≥50 years of age group was not statistically significant (CI: -15, 51). 

Overall VE for Influenza A/H1N1pdm09 was 46% (CI: 30, 58). By age group, VE was 62% (CI: 

40, 75) for children 6 months through 17 years of age, 45% (CI: 14, 64) for adults 18 through 49 

years of age, and 8% (CI: -59, 46) for adults ≥50 years of age. Again, the confidence interval for 

the ≥50 years of age group was not statistically significant. The age groups depend upon 

whether there are enough samples to be able to divide into age groups and have confidence in 

the estimates. This was possible for these interim estimates for A/H1N1, but not for A/H3N2. 

Overall VE for all ages for A/H3N2 was 44% (CI: 13, 64).

In Summary, interim results for 2018-2019 season through February 2, 2019 indicate protection 

against influenza at 47% (CI: 35, 57) VE overall against any influenza virus, 46% (CI: 30, 58) 

against H1N1pdm09, and 44% (CI: 13, 64) against H3N2. Effectiveness estimates among 

children aged 6 months through 17 years was 61% (CI: 44, 73) against any influenza, and 62% 

(CI: 40, 75) against H1N1pdm09. Effectiveness estimates ranged from 37% to 45% among 

adults aged 18 through 49 years. Effectiveness estimates were not statistically significant 

among those ≥50 years. The US Flu VE study will continue enrolling through the end of the 

season. To put these in context, there are some recently published estimates of 2018-2019 VE 

from several networks shown here:

Canada, Skowronski et al, Eurosurveillance 2019

VE 68% (CI: 55, 77) against any influenza, 72% against H1N1pdm09

Europe, Kissling et al, Eurosurveillance 2019

VE 32% – 43% against influenza A, 45% – 71% against H1N1pdm09

UK, LAIV: VE 87% (CI: 4, 100) against H1N1pdm09

Hong Kong, Chiu et al, Eurosurveillance 2019

Inpatient VE 92% (CI: 82, 96) against H1N1pdm09, 6m-17 years 

Australia (2018), Australian Government website

VE 78% (CI: 51, 91) against H1N1pdm09, all ages

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To put US estimates in context, CDC has begun posting estimates of disease burden on the 

CDC website. These pyramids are shown on the website:

In the first graphic above, the box on the right shows the recent A(H1N1)pdm09 predominant 

seasons, 2013-2014 and 2015-2016. For comparison, the numbers for A(H1N1)pdm09 

predominant seasons fall somewhere in the middle of this range that has been seen since 2010. 

The second graphic combines end-of-season VE estimates together with burden averted. These 

results were published in January 2019 in Clinical Infectious Diseases. This same approach will 

be taken for end-of-season VE and disease burden as soon as those data are available later 

this fall. The substantial numbers of disease burden averted last season were based on a 

vaccine coverage that is within the range seen for this season and a VE of about 38%—again, 

the range seen for the interim estimates. 

Discussion Points

Dr. Romero asked whether there are any data on live attenuated influenza vaccine (LAIV) VE in 

the US, whether there is enough use of LAIV such that there will be some reasonable and 

trustworthy VE data at the end of the season, and whether there are any variations in 

susceptibility to antivirals given in terms of the A(H3N2) viruses and the intra-clade variation.

Dr. Flannery replied that there is not very much LAIV use in the US Flu VE Network sites. It is 

questionable whether there will be enough at the end of the season to be able to provide LAIVspecific estimates. For the interim estimates, only a handful of children have received LAIV.

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Regarding susceptibility of the A(H3N2) viruses to antivirals, Dr. Brammer indicated that all 

viruses tested so far this year have been susceptible to all antivirals.

Dr. Szilagyi asked whether in addition to the United Kingdom (UK) there is much LAIV use in 

other countries.

Dr. Flannery replied that the information he has is that there are several countries that have 

used LAIV in the past that continue to use LAIV, and that there may be some estimates from 

Finland and others. LAIV use in Canada has reportedly been very low. 

Dr. Allyn Bandell (Senior Director, Medical Affairs, AstraZeneca) indicated that VE estimates for 

LAIV are anticipated from Finland, the UK, possibly Hong Kong, and Canada. Some of those 

data are expected to be presented during the European Society for Paediatric Infectious 

Diseases (ESPID) meeting in the European Union (EU) in May.

Dr. Quach (NACI) reported that Canada has not stopped using LAIV, but there is not much use. 

If they do have an estimate, it is not anticipated to be statistically significant in any way.

Dr. Walter asked whether there were any thoughts regarding the potential downstream effects 

of the delay in strain selection in terms of manufacturing and availability of vaccine.

Dr. Fink (FDA) indicated that as mentioned, VRBPAC would be meeting the next week and 

likely would not be able to make a recommendation on the H3N2 selection. Beyond that, he 

could not comment further on the potential downstream implications.

Dr. Bernstein observed that VE for LAIV in the UK was encouraging and wondered how that 

population compares to the US population in terms of use and ages, and whether it is 

administered to school-aged children only.

Dr. Flannery indicated that there was a recent paper from Huong Q. McLean et al at Marshfield 

Clinic that examines prior season vaccination, which does not seem to indicate that prior season 

vaccination was one of the major contributors to what was observed in the US with low VE. 

There was some speculation at the time about the UK population being less vaccinated than the 

US population, but the children in the LAIV group in the UK have received vaccine over several 

seasons with predominantly LAIV. The program rollout in the UK is now in its 6th year, with a 

large population vaccinated. The population is slightly different in terms of repeat vaccination 

with LAIV, but is similar in that the population has now been vaccinated several different 

seasons. The UK program is widely school-based, but there is a program for children from the 

age of 2 years.

Dr. Stephens was curious about the WHO recommendation for change in the H1N1 component, 

given the HI data of very good protection in the US. He wondered whether there were data 

outside of the US pertaining to H1N1.

Dr. Brammer said she thought the decision was made based primarily on the fact that even 

though it is known that there are genetic changes occurring within the H1N1 viruses and the 

data look good with ferret antisera, reduced titers were seen with human sera.

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Dr. Jackie Katz (CDC, Influenza Division) added that the recommendation was based on the 

fact that over the last 18 months or so, there has been an accumulation of genetic changes—

one change in each of 3 antigenic groups. In the last 6 months or so, there has been an 

additional change that appears to be sweeping through the H1N1pdm09 virus population as 

have the other 3. Collectively, it seems that there is a selection for these particular substitutions. 

As noted, antigenic changes were not observed using ferret antisera. As a reminder, there was 

a similar situation when the change was made to A/Michigan/45/2015 a couple of years ago. 

They also assessed panels of pre- and post-vaccination serum from individuals of various age 

groups who have received the current 2018-2019 season’s vaccine and noted that the postvaccination GMTs in multiple populations were substantially reduced against the recent viruses 

that have 183P in addition to the other changes. That substantial reduction was seen in some 

individual pediatric sera as well. This was thought to be an indication that the virus was on the 

move and that an updated recommendation should be made.

Dr. Frey observed that the estimates Dr. Flannery shared from other countries seemed to be 

higher than US estimates, LAIV aside, and wondered what would explain this difference (e.g., 

strain change, vaccine type, use of adjuvant, low numbers, et cetera).

Dr. Flannery indicated that the one caveat for all of these estimates was that they were interim 

and the confidence intervals were wide. While the interim numbers from Canada were perhaps 

encouraging in that they were high overall and also by age group, the numbers were small. The 

US did not feel confident breaking out the estimates for adults ≥65 years, which is why it was 

presented as ≥50 years. For the European estimates just published, the overall estimates from 

4 different studies were within the range that are seen in the US. There was some heterogeneity 

in the age-specific group, again with small numbers. While a caveat is that the US does not 

have a lot of cases in the ≥50 years of age population at this point in the season, there may be a 

change in those estimates as the seasons goes on.

Dr. Szilagyi appreciated seeing the slide on deaths, hospitalizations, and cases averted. Data 

are often presented on the burden of disease, but are presented infrequently on diseases that 

are actually averted by vaccinations. If they could acquire New Vaccine Surveillance Network 

(NVSN) data, he suggested adding emergency department (ED) visits averted as well as direct 

and indirect costs averted by the vaccination program. He emphasized that while he raised this 

specifically regarding influenza, he thought this would be useful for other vaccines as well.

Dr. Bernstein asked whether the percent of vaccine receipt was known for those who had died.

Dr. Brammer replied that while they do not have this information for the general population, the 

proportion of children fully vaccinated among influenza-associated pediatric deaths is very 

similar to what is typically observed annually at about 20%.

Dr. Kimberlin (AAP) inquired as to whether anyone could comment on the Baloxavir experience 

in Japan and the rapid emergence of resistance, and whether that is being monitored in the US 

and the amount of Baloxavir use in the US. He emphasized the need to follow this carefully.

Dr. Jackie Katz (CDC, Influenza Division) indicated that the likelihood of resistance in the US is 

being monitored, and there has been one example in a treated case. However, she said she 

could not speak to the amount of use in the US.

Dr. Foster (APhA) asked whether any changes had been observed in the uptake of vaccine this 

year, particularly given that last year was such a bad season.

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Dr. Flannery indicated that there are some early estimates of vaccine uptake on the CDC 

website, which suggest that there was an uptick. A caveat with that is that there have been 

some changes in how immunization coverage is being monitored and estimated. He invited 

additional information from the Immunization Services Division (ISD).

Dr. Wharton (Division Director, ISD) indicated that the National Immunization Survey (NIS) data 

have shown an increase in pediatric influenza vaccination coverage.

Dr. Lee asked whether there would be any estimates on the burden of disease in pregnant 

women.

Dr. Alicia Fry (SME) reported that a special study is being conducted for last season, which 

hopefully will be published before this season’s estimate is available. CDC is working on this.

Afluria® Quadrivalent Influenza Vaccine (QIV) Phase III, Randomized, 

Observer-Blind Comparator-Controlled Study Among Children 6-59 Months

Gregg C. Sylvester, MD, MPH

Medical Affairs

SeqirusTM

Dr. Sylvester presented the results from Seqirus’sTM Phase III trial for its QIV inactivated split 

virion influenza vaccine, Afluria® QIV, among children 6 through 59 months of age. The 

SeqirusTM trivalent influenza vaccine (TIV) formulation used in the Southern Hemisphere during 

the 2010 influenza season was associated with increased reports of fevers and febrile seizures

in children, especially those less than 5 years of age. As a result, Afluria® TIV was not 

recommended for continued use in this age group. Investigations by SeqirusTM identified 

residual lipid under the previous manufacturing conditions as a likely cause of the fevers. In vitro 

studies showed that increasing the concentration of the splitting agent reduced the lipid content 

and pyrogenicity of the vaccine.

Accordingly, the concentration of the splitting agent used in the manufacturing process for 

Afluria® QIV was increased. SeqirusTM took a stepwise approach to license Afluria® QIV. For 

2014-2015, an Afluria® QIV Phase III randomized controlled trial (RCT) in adults ≥ 18 years of 

age was approved by the FDA in August 2016. For 2015-2016, an Afluria® QIV Phase III RCT in 

children 5 to <18 years of age was approved by the FDA in August 2017. For 2016-2017, 

Afluria® QIV Phase III RCT in children 6 months to <5 years of age was approved by the FDA in 

October 2018.

In the study among children 6 months to <5 years of age, SeqirusTM evaluated the 

immunogenicity and safety of Afluria® QIV compared to a US licensed influenza vaccine, both 

containing the 4 influenza strains recommended that season. The study was conducted at 39 

US sites between September 2016 and August 2017. The protocol was approved by the 

Institutional Review Boards (IRBs). Randomization was characterized by a younger cohort ages 

6 to 35 months (n=935) and an older cohort ages 36 to 59 months of age (n=1312). Participants 

were randomized 3:1 to receive Afluria® QIV or the comparator influenza vaccine. Participants 

received 1 or 2 doses based upon their influenza history. The younger cohort received a 0.25 

mL dose of vaccine and the older cohort received a 0.5 mL dose of vaccine.

The primary immunogenicity objective was to demonstrate that vaccination with Afluria® QIV

elicits an immune response that is non-inferior compared to a US-licensed influenza vaccine. 

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The primary safety objective was to describe the tolerability of Afluria® QIV compared to the 

comparator vaccines, especially noting fever rates.

Healthy children in the specified age group were enrolled in the study. Children were excluded if 

they were febrile, acutely ill, immunocompromised, or allergic to any component of either 

vaccine. Children also were excluded if they had a history of SAEs to any influenza vaccine; 

history of seizure, with the exception of simple febrile seizures; or had received any vaccine 

within 21 days. This study was not designed to assess co-administration with other childhood 

vaccines. SeqirusTM wanted to study the safety profile of Afluria® QIV alone. The demographics 

and baseline characteristics are well-balanced within the two groups and within the two age 

cohorts. The mean age is slightly over 3 years. There are slightly more boys in the study than 

girls. African Americans are well-represented, but Asians are under-represented. The prevaccine temperature median was all within the normal range. Approximately 40% of all 

participants were indicated for 2 doses, which was higher in the younger age group and lower in 

the older age group.

A non-inferiority immunogenicity study design was used, with 8 co-primary endpoints to gain 

licensure in the US. GMTs and seroconversion rates (SCR) were analyzed for the 4 viral strains. 

These endpoints were defined in accordance with the FDA guidance for non-inferiority studies, 

and are commonly used in the evaluation of efficacy of influenza vaccines. For GMTs, the upper 

bound of the 2-sided 95% CI of the GMT ratios should not exceed 1.5. For SCR, the upper 

bound of the 2-sided 95% CI of the SCR differences should be ≤10%. If all 8 co-primary 

endpoints meet the prespecified FDA criteria, then non-inferiority for Afluria® QIV compared to 

the US comparator influenza vaccine can be concluded. 

In terms of the results, the GMT ratios were similar between vaccines. The upper bound of the 

95% CI did not exceed the prespecified margin of 1.5. The SCR were similar, and the difference 

of ≤10% between vaccines met the prespecified criteria. Immune responses were similar across 

the two age groups and within the two vaccine groups. The primary co-endpoints, measured by 

GMTs and SCRs, for each of the viral strains were met.

Solicited AEs are collected for 7 days post-vaccination by e-diaries, telephone calls, and clinic 

or ED visits. The categories for local AEs are Mild/Grade 1 AEs that do not interfere with daily 

activity, Moderate/Grade 2 that involves pain resulting in crying upon touch, and Severe/Grade 

3 that involves crying when the limb is moved. In the younger cohort, local reactions were 

similar between both vaccine groups and most reactions were mild or moderate. In the older 

cohort, the same 3 symptoms were assessed, the reactions were similar between both vaccine 

groups, and most reactions were mild or moderate. In the younger and older cohorts, the vast 

majority of local reactions resolved within 2 days of vaccination.

The AEs for solicited systemic AEs are irritability, diarrhea, loss of appetite, and 

nausea/vomiting. The pain categories are Mild for AEs that are easily tolerated, minimal 

discomfort, and does not interfere with any daily activity; Moderate for AEs that are sufficiently 

discomforting and can interfere with daily activity; and Severe for AEs that are severe and 

prevent daily activity or requires significant medical intervention. Like the local reactions, the 

systemic events in the younger cohort were similar between both vaccine groups, most were 

mild or moderate, and there were very few severe events. In the older cohort, solicited systemic 

AEs were seen in 5% or more of the older cohort. Once again, the events were similar between 

the groups and were mild or moderate in intensity.

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The categories for fever events were Mild (99.5 °F to <100.4 °F), Moderate (≥ 100.4 °F to 101.3 

°F), and Severe (≥ 101.3°F). The overall fever rate for Afluria® QIV was 7.2% versus 11.9% for 

the comparator. Severe related fevers were similar between the two vaccine groups. When the 

Mild, Moderate, and Severe categories are combined for the overall related fever group, only 

4% of the subjects given Afluria® QIV had a fever related to the vaccine versus 7.9% of the 

subjects given the comparator. In the older cohort, the Afluria® QIV overall for any fever rate 

was 4.8% versus the comparator of 6.0%. Severe related fevers were similar between the two 

vaccine groups, with an overall related fever rate of 3.1% for Afluria® QIV versus 4.7% in the 

comparator. In both age groups, most fevers had onset within Day 1 to Day 3 following 

vaccination. 

There were 11 SAEs by the end of the study in the younger cohort for Afluria® QIV. These 11 

events were all determined to be unrelated to the vaccine by the study investigators and by an 

independent Data and Safety Monitoring Board (DSMB). There were 2 Adverse Events of 

Special Interest (AESIs). Both children were classified as having a simple febrile seizure, one of 

which occurred at Day 43 and the other of which occurred at Day 103 of the study. Neither child 

was febrile during the 7 days post-vaccination, which is considered the risk window for febrile 

seizures related to influenza vaccination. These 2 AESIs also were determined to be unrelated 

to Afluria® QIV.

In this study of children 6 months through 59 months of age, similar immune responses were 

demonstrated for Afluria® QIV and the US licensed influenza comparator vaccine for all 4 strains 

as assessed by GMTs and SCRs. The safety and tolerability of Afluria® QIV is similar to the 

comparator vaccine in children <5 years of age. The overall any fever ( ≥ 99.5 °F) rate for 

Afluria® QIV was 7.2% and 11.9% for the comparator. There were no febrile seizures during the 

first 7 days, and severe related fever are similar between the two groups in both age groups. 

The FDA criteria for non-inferiority was met for all 8 co-primary endpoints and thus, Seqirus’sTM

received approval for licensure on October 31, 2018 for the new age group of 6 month through 

59 months.

Discussion Points

Dr. Bernstein inquired as to how much Afluria® QIV is used in the US in the younger age group.

Dr. Sylvester indicated that no Afluria® QIV is used in the younger age group, because it was 

just licensed. Prior to that, it had not been recommended. It was this clinical trial that 

demonstrates that it is safe and effective in this age group. The plan is to use Afluria® QIV in the 

upcoming influenza season.

Dr. Moore pointed out that it is always great to have additional products becoming available for 

younger age groups, and wondered whether there are future phased studies that will assess the 

0.5 mL dosing in the 6 month to 35 month group. While the dose was 0.25 mL at the time this 

study was designed, other manufacturers with similar products have now moved up to the 0.5 

mL dose, which is very popular programmatically because it simplifies inventory management 

and dosing and prevents administration errors.

Dr. Sylvester indicated that they wanted to assess the 0.25 mL dose because of the issue of 

fever in 2010. They are discussing internally whether there are opportunities to study Afluria®

QIV in the 6 month to 35 month group at a higher dose.

Dr. O’Leary (PIDS) requested further information about the SAEs at Day 28.

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Dr. Sylvester indicated that of the 11 SAEs among Afluria® QIV recipients, there were the 2 

febrile seizures mentioned earlier, 3 respiratory syncytial virus (RSV) infections, 2 croup 

infections, 1 dysphasia, 1 dehydration, 1 foreign body aspiration, and 1 animal bite. Among the 

3 that occurred in the comparator group, 1 was a broken arm, 1 was bronchiolitis, and 1 was 

impaired gastric emptying.

Case-Control Study of Inactivated Influenza Vaccine and Spontaneous 

Abortion in the Vaccine Safety Datalink, 2012-13, 2013-14, and 2014-15

Jim Donahue, PhD, DVM

Marshfield Clinic Research Institute

Dr. Donahue reported on a recently completed case-control study of IIV and SAB in the VSD, 

which covered 3 seasons: 2012-2013, 2013-2014, and 2014-2015. This is the third case-control 

study. Matched case-control studies were conducted in women who were pregnant in 2005-

2006 and 2006-2007 in the VSD, which did not find an association between SAB and IIV receipt 

in a 28-day risk window. The odds ratio was 1.2 and the 95% CI included 1.0 [Irving, Obst Gyn 

2013].

After the 2009 pandemic, CDC funded another matched case-control study in the VSD to 

examine the association between SAB and influenza vaccination during the 2010-2011 season, 

the first full season after the 2009 pandemic, and the 2011-2012 season. The design was 

similar, with individual matching by VSD site, maternal age group, date of last menstrual period 

(LMP). Chart reviews were done for all cases and controls. Vaccine association with SAB was 

assessed in 3 risk windows: before SAB: 1-28 days (primary), 29-56 days, and >56 days. In that 

study, the results were somewhat different. SAB was associated with IIV receipt in the 28 day 

risk window (odds ratio=2.0, 95% CI 1.1-3.6). No other associations were found in any other risk 

windows. IIV-SAB association was statistically significant in 2010-2011 but not in 2011-2012. In 

both seasons, statistically significant associations were found only in women who had received 

influenza vaccine in the prior influenza season. This is suggestive of an effect modification, but 

this was only in the 1-28 day window. A number of additional analyses were performed to try to 

figure out whether there was some bias or confounding, but nothing could be clearly attributed 

to bias or confounding.

For the current study, they wanted to focus on the effect modification question regarding 

whether being vaccinated in the previous season was somehow influencing the relationship 

between current season vaccination and SAB. The two main objectives were to: 1) evaluate the 

IIV-SAB association in the 28 days before SAB among women who received influenza vaccine 

during the prior season; and 2) evaluate the IIV-SAB association in the 28 days before the SAB 

among women who did not receive the vaccine during the prior season. The secondary 

objectives were to: 1) evaluate the IIV-SAB association for vaccine receipt relative to 

conception; and 2) evaluate the association in each of the three seasons.

They were fortunate to have input from two scientific advisory groups for this study. The first 

one, comprised of VSD and CDC scientists, met in late 2015 primarily to advise on study 

design. The second was a subgroup of the Influenza WG of the ACIP, the Maternal Influenza 

Vaccination Safety Sub-WG. This group was comprised of epidemiologists, biostatisticians, and 

clinicians. The mission was to provide advice on the analytic plan and recommendations to 

enhance the interpretability of the results. The 6 VSD sites that participated in this study 

included: Kaiser Colorado, Kaiser Northern California, Kaiser Northwest, Kaiser Southern

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California, Kaiser Washington, and Marshfield Clinic. These are the same sites as in the 

previous study.

The study design, a matched case-control, was similar to the previous two studies. The subjects 

were matched on age group (18-24, 25-34, 35-44), site, LMP, and influenza vaccination status 

in the previous season (which differed from the last study). Also different in this study was that 

50% of the cases in each season were vaccinated in the previous influenza season. Eligibility 

criteria were close to the same as before and included adults 18 to 44 years of age as of LMP, 

individuals who were enrolled in VSD site ≥ 20 months prior to LMP (which differed from the last 

study, which was 12 months), LMP has to be documented in the record, and SAB (cases) or live 

birth (controls) had to be confirmed.

Potential cases were identified using International Classification of Diseases (ICD)-9 codes 

assigned during influenza season. Medical record review and adjudication were done for all 

potential cases. For the primary analysis in this study, SAB was defined as occurring between 6 

to <20 weeks gestational age. A secondary analysis was performed in which the date of SAB 

was increased between 5 to <20 weeks gestational age. The date of SAB was considered to be 

the reference date for each case-control pair. Controls were identified in a similar way using a 

VSD pregnancy database or ICD-9/ICD-10 codes for live births. Vaccine exposures were 

documented from the medical record. The primary risk window was the 28 days before the 

reference date. Other risk windows included 29-56 and >56 days. The secondary analysis

windows were relative to conception, with 4 windows: >42 days before, 0-42 days before, 1-28 

days after (and before the reference date), and >28 days after (and before the reference date). 

Extensive review was done to try to determine the data of SAB and gestational age. All cases 

were adjudicated to confirm SAB and estimate gestational age and date of SAB, and were 

blinded to vaccination status. The adjudication process was under the direction of the 

obstetrician co-investigator and followed the established adjudication algorithm that was used in 

the previous study, though it was somewhat more polished in this study. In addition to the 

algorithm, the estimate incorporates information from medical records: U/S data, clinical events 

(e.g., hemorrhaging), LMP, ICD coding, et cetera.

Because this was a matched case-control study, conditional logistic regression was done. The 

referent group for all of the estimates were women not vaccinated as of the reference date. 

Separate models were done for women with and without prior season vaccination, and all 

women combined. Confounding was assessed separately for each model. Five variables were 

included in all 3 of those models: maternal age, body mass index (BMI), and health care 

utilization represented as natural cubic splines, race, and ethnicity. The other covariates differ 

for different models depending upon the bivariate analysis that was done. When planning for 

this study, it was important to determine the ability to detect an odd ratio in the stratum-specific 

and season-specific estimates. If there were 250 matched pairs in each stratum and season, 

there would be 82% power to detect an odd ratio of 3.5. If some of the strata could be combined 

for 500 matched pairs in each season, there would be 82% power to detect an odds ratio of 2.3. 

If strata and season could all be combined, 1500 matched pairs would provide 83% power for 

an odds ratio of 1.6. They identified a little less than 1400 pairs.

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Matched pairs and controls were identified beginning with 1908 presumptive cases of SAB. 

After eliminating 166 who had outcomes other than SAB, there were 1634 confirmed SABs. The 

adjudication process eliminated another 224 of those, leaving 1410. It was not possible to match 

29 of those, which left 1381 cases between 5 and <20 weeks. The <6 weeks gestational age 

cases were eliminated leaving 1236 matched pairs, which was the primary group analyzed for 

the study.

Regarding descriptive characteristics among vaccinated and non-vaccinated cases in the 

previous season, cases were slightly older than controls. That was particularly true in the 40 to 

44 age group. Cases also had a somewhat higher BMI than controls in both strata. Cases were 

more likely to be African American and Hispanic and less likely to be Asian. At least in women 

who were vaccinated in the previous season, cases were more likely to have diabetes and 

asthma. Within the two strata, cases and controls had pretty similar proportions in terms of 

having had 1 or 2 previous SABs.

In terms of the frequency of vaccination exposures for cases and controls, if there had been an 

association between vaccine and SAB, the numbers in the risk window of 1-28 days, a greater 

number of cases would have been expected to have been vaccinated proportionately than 

controls. However, this was not the case in any of the 3 seasons. For the 1-28 day window 

among those who were vaccinated in the previous season in 2012-2013, the odds ratio was 0.5 

(0.2, 1.1), in 2013-2014 the odds ratio was 1.1 (0.6, 2.3), and in 2014-2015 it was 1.7 (0.7, 4.0). 

In the other two risk windows of 29-56 and >56 among those vaccinated in the previous season, 

all of the odds ratios were less than or close to 1. For those who were not vaccinated in the 

previous season in the 1-28 day risk window, all of the odds ratios were pretty close to or less 

than 1. In 2012-2013, the odds ratio was 0.7 (0.3, 1.6), in 2013-2014 it was 0.6 (0.2, 1.4), and in 

2014-2015 it was 0.7 (0.3, 1.8). In the 2014-2015 season, there were slightly elevated odds 

ratios in the group vaccinated in the previous season of 1.7 (0.7, 4.0) in the 1-28 day risk 

window. There also were slightly elevated odds in the 2012-2013 season in the not vaccinated 

group of 1.8 (0.2, 14.9) in the 29-56 risk window, with very wide confidence intervals and small 

discordant pairs of 2/2.

Because there did not appear to be any season-specific differences, all 3 seasons were 

combined for odds ratios less than 1.0 in both the vaccinated in the previous season and 

unvaccinated in the previous season groups. Because there did not appear to be an effective 

modification by prior vaccination, the two strata were combined. This resulted in odds ratios of 

less than or close to 1.0 and in all cases, and confidence intervals that include 1.0 in all cases 

for each of the 3 seasons. Combining all seasons and both strata, the adjusted odds ratios were 

all less than 1.0. Those were all exposures in the 3 risk windows that were before the reference 

data.

The secondary analysis examined exposures relative to conception. This time the risk window 

strata for days between vaccination and conception were: >42 before, 0-42 before, 1-28 after, 

>28 after. For the most part, the adjusted odds ratios were less than and close to 1.0. To 

highlight a couple that were somewhat higher, in the 2014-2015 season among those 

vaccinated in the previous season, the odds ratio was 2.1 (0.8, 5.2) in the 1-28 days after 

conception risk window. In the 2012-2013 season among those not vaccinated in the previous 

season, the odds ratio was 3.2 (0.9, 11.9) in the 1-28 days after risk window. Combining the 

seasons, the adjusted odds ratios ranged from 0.5 to 1.1 in both strata.

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Additional secondary analyses were done because the definition for SAB in the previous study 

was a gestational age between 5 and <20 weeks in the previous study. The results were 

essentially the same when gestational age range expanded to include 5 to <20 weeks, and 

when another analysis was performed that excluded women with history of ≥2 SABs.

Comparing the third IIV-SAB study with the previous 2 IIV-SAB studies, and few differences 

were found between the 3 populations. Some differences that stand out are that the IIV-SAB-3 

2012-15 study included women who were about 2 years older than women in the previous 2 

studies, and there were fewer smokers among the women in the third study. The median 

gestational age at the time of the SAB was almost identical in all 3 studies. Most of the other 

characteristics were fairly similar. The gestational age at the time of SAB in the third study was 

compared to the IIV-SAB-2 2010-2012 study, and the overall distribution was similar. However, 

the prior study had more women in the 6-week gestational age range and the third study had 

more in the 7-8 week range. Both studies had a median gestational age of 7 weeks (IQR 6, 9).

There were some differences in terms of the results. There were methodologic differences 

between the current and prior VSD study, including different seasons (2012-2013, 2013-2014, 

and 2014-2015), the current study was matched on previous season influenza vaccination 

status, the current study was matched on 3 age groups (18-24, 25-34, and 35-44 years) rather 

than 2 age groups, and the study population was approximately 3 times larger compared to the 

prior study (2762 vs. 970).

The major findings of the third study were that there was no significant association between 

influenza vaccine receipt and SAB, regardless of prior season vaccination status. Odds ratios 

were less than or close to 1.0 in all risk windows. For the odds ratios that were greater than 1.0, 

the 95% confidence intervals included 1.0 in each case. There were no significant associations 

in the season-specific analyses. These findings support the current recommendation for 

vaccination of pregnant women in any stage of pregnancy.

Discussion Points

Dr. Szilagyi observed that this was a very elegant presentation of a complex study. He asked 

whether Dr. Donahue had any additional thoughts about the prior study, recalling that he had 

mentioned when the second study was presented to ACIP that it was not an optimally designed 

study and there were some potential problems. Having now studied this matching for prior 

vaccination and a much larger sample size provides a lot of comfort, but having rethought the 

prior study, he wondered if there were any additional explanations.

Dr. Donahue indicated that the design changes they made for this study were important and 

allowed them to focus on the effect modification issue. He did not think it would have changed 

anything had they done this in the previous study. They cannot really explain why those results 

were different. Perhaps it is random variation, different time periods, further removed from the 

2009 pandemic, a 3 times larger study population to allow for examination of the effect 

modification, and/or relevance to women who are pregnant now. The design of the third study 

was not intended to either confirm or refute the results of the previous study.

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Summary and Work Group Considerations

Lisa Grohskopf, MD, MPH 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

In addition to the WG members, Dr. Grohskopf recognized and appreciated the various CDC 

staff who make a regular and important contribution to the discussion. She then briefly 

summarized some of the WG discussions and described plans for the next few months.

Regarding influenza vaccines for young children, primarily 6 months through 35 months of age, 

there have been a number of recent licensure changes. During this session, they heard the 

presentation on Afluria®. In October 2018, FDA licensed both Afluria® TIV and Afluria® QIV for 

children ≥6 months of age, which was a change from the ≥5 years of age. The dose for children 

6 through 35 months of age is smaller at 0.25mL versus 0.5mL for those aged ≥3 years. There 

was also discussion during the October 2018 ACIP meeting on Fluzone® Quadrivalent data. 

This has been licensed for children 6 through 35 months for some time. For a number of 

seasons until relatively recently, this was the only influenza vaccine licensed for this age group. 

It was originally licensed at 0.25mL/dose. As of January 2019, FDA licensed 0.5mL/dose for all 

ages based on the results of a randomized non-inferiority trial of immunogenicity and safety of 

0.25mL vs. 0.5mL in children aged 6 through 35 months presented to ACIP in October 2018. 

Per the labeling for this vaccine, either 0.25mL or 0.5mL is acceptable for children 6 through 35 

months of age.

One of the questions asked when this age groups is discussed regards what the experience is 

with concomitant vaccination. Younger children are more likely to have febrile reactions to 

vaccines. With the newer age indications, expansions of age indications, and dose changes 

there is overall less cumulative experience with this in terms of this age group. Conversely, the 

clinical data and clinical study data that have been accumulated thus far is reassuring. Another 

point that was discussed is that there are now five licensed IIV vaccines that are licensed for 6 

through 35 months of age, but the dose volumes differ as shown in the table below:

Vaccine Dose Volume

Fluarix® Quadrivalent (IIV4, GSK) 0.5mL

FluLaval

® Quadrivalent (IIV4, ID Biomedical Corp/GSK) 0.5mL

Fluzone® Quadrivalent (IIV4, Sanofi Pasteur) 0.25 mL or 0.5 mL

Afluria®(IIV3, Seqirus) 0.25 mL

Afluria® Quadrivalent (IIV4, Seqirus) 0.25 mL

Fluarix® Quadrivalent and FluLaval® Quadrivalent were initially licensed for ≥3 years. and 

FluLaval® Quadrivalent had an age expansion to ≥6 months in November 2016 and Fluarix®

Quadrivalent in January 2019 at the 0.5mL, which is the same dose as persons aged ≥3 years. 

It will be important to focus on this moving forward, depending upon the vaccines expected to 

be available next season, in terms of providing guidance to ensure avoiding the potential for 

confusion.

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With regard to the VSD study, the WG discussed the differences between the current and the 

previous IIV and SAB studies in terms of methodology, matching, study size and statistical 

power, and available vaccines during the different periods. Overall, the results were felt to be 

reassuring. 

Between now and the June 2019 meeting, the development of the 2019-2020 ACIP Influenza 

Statement will be ongoing. There will probably be some further discussion during the June 2019 

ACIP meeting. Based on what is known currently, no substantial changes are anticipated, and 

the anticipated publication date is August 2019. The WG continues the discussion of 2018-2019 

influenza VE data. As mentioned earlier, no estimates of LAIV effectiveness are anticipated this 

season from the US Flu VE Network as there may not be sufficient utilization of LAIV in the US 

to be able to do that. The WG will continue to follow what is occurring in other countries that use 

LAIV. As is typically done during the June ACIP meetings, a general influenza vaccine safety 

update is anticipated to be presented during the June 2019 meeting.

Discussion Points

Dr. Maldonado (AAP) expressed AAP’s concern with providers asking about a preference 

because there are 2 different doses of Fluzone® Quadrivalent (IIV4, Sanofi Pasteur) of 0.25 mL 

or 0.5 mL, and she wondered whether there were plans to phase out the lower dose or if both 

would continue to be on the market.

Dr. Grohskopf indicated that as the WG understands it, the study submitted to FDA for licensure 

for the 0.5 mL was a non-inferiority study. Therefore, it might be difficult to have a discussion 

about a preference for one or the other dose. The question regarding whether the lower dose 

would continue to be on the market would be best directed to the manufacturer.

Julian Ritchey (Sanofi Pasteur) indicated that they plan to manufacture the 0.25 mL dose as 

long as there is sufficient demand, which is part of the overall calculation for influenza in the prebooking process. They will anticipate it being available as long as physicians would like it, 

because they view it both as a convenience and a practice opportunity.

Ms. Hayes (ACNM) asked whether new data on pregnant women were provided to the FDA in 

the recent approval on Fluzone® Quadrivalent being safe in pregnancy.

Dr. Grohskopf said she was not aware of any changes, but that perhaps the FDA representative 

could respond.

Dr. Fink (FDA) indicated that there have been no changes to any FDA licensure of the vaccine 

with respect to pregnancy. It is not contraindicated in pregnancy, but it is not indicated 

specifically for use in pregnancy.

Dr. Ezeanolue inquired as to whether a Sanofi Pasteur representative could further address the 

question regarding the 0.25 mL or 0.5 mL doses in terms of whether there is an advantage of 

one over the other.

Julian Ritchey (Sanofi Pasteur) indicated that he did not have any additional information, given 

that it was a non-inferiority study. It does not really provide a conclusion about the ability to 

make a recommendation of one over the other. This was done as a response to the physician 

and office preference. While they would be happy to further discuss it, the data are limited at 

this point in the ability to make a conclusion.

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Introduction

Peter Szilagyi, MD, MPH

Chair, ACIP HPV Vaccines WG

Dr. Szilagyi indicated that the human papillomavirus (HPV) vaccination policy issue being 

addressed by the WG is, “Should HPV vaccination be recommended for persons aged 27 

through 45 years who were not previously vaccinated?” There is an expanded age indication for 

9-valent HPV (9vHPV) vaccine. The manufacturer filed a Supplemental Biologics License 

Application (sBLA) in April 2018 to expand the age indication for 9vHPV vaccine from age 9-26 

years to age 9-45 years. This was approved by FDA in October 2018. As a reminder, the 

9vHPV vaccine is the only HPV vaccine currently available in the US.

To recap the past two ACIP HPV sessions, there have been some significant policy discussions 

about HPV. In June, there was an overview and presentation on the history of the application for

licensure in mid-adults; a review of HPV epidemiology, natural history, and burden of disease; 

and a presentation on the clinical trial data that was included in the sBLA. In October 2018, 

presentations included a review of the regulatory basis for licensure and several aspects of the 

US HPV vaccination program, including vaccine coverage and the impact on infection and 

disease. There were reviews of HPV epidemiology and sexual behavior, post-licensure 

effectiveness studies, and global HPV vaccination and vaccine supply. GRADE also was 

reviewed for efficacy, immunogenicity, and safety of mid-adult vaccination. There also was a 

review of preliminary health economic analyses, and discussion of some policy considerations.

Since October, the HPV Vaccine WG has been very active. Topics reviewed that relate to midadult vaccination since October 2018 include impact modeling and health economic analyses, 

HPV epidemiology and natural history, values and acceptability to stakeholders, and 

recommendation options for consideration. In terms of the modeling and health economic 

analyses for mid-adult HPV vaccination, 3 models were initially providing evidence for this policy 

question. All were going through CDC/ACIP economic review at the time of the October 

meeting, and the economic review is still ongoing. There are differences in results across 

models, with preliminary data presented at the October 2018 ACIP meeting. Several WG calls 

have been devoted to reviewing the results of these models.

Dr. Szilagyi indicated that this session would include presentations on the following topics:

❑

❑

❑

❑

❑

❑

Overview and Background 

Impact and Cost Effectiveness, Mid-Adult HPV Vaccination 

Overview of Health Economic Results from 4 Modeling Groups 

Mid-Adult HPV Vaccination: Patient Values and Acceptability

Program and Vaccine Provider Surveys 

WG Considerations

Human Papillomavirus (HPV) Vaccines

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Overview and Background Expanded Age Indication for 9vHPV Vaccine

Lauri Markowitz, MD 

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Markowitz indicated that the purpose of this presentation was to provide some background 

for the subsequent two modeling presentations, and describe some of the uncertainties 

regarding HPV epidemiology and natural history that impact considerations for mid-adult HPV 

vaccination.

As a reminder, the current recommendations for HPV vaccination in the US are routine 

vaccination at age 11 or 12 years; catch-up vaccination for females through age 26 years and 

males through age 21 years, as well as certain populations (e.g., MSM, transgender persons, 

and persons with certain immunocompromising conditions) through age 26 years; and males 

aged 22 through 26 years may be vaccinated [MMWR 2014;63 (RR05), MMWR 2015;64:300-4, 

MMWR 2016; 65:2105-8].

From WG discussions of mid-adult vaccination, Dr. Markowitz highlighted that the WG affirms 

the importance of adolescent HPV vaccination and the primary focus of the immunization

program on this age group. Regarding vaccination for mid-adults, vaccination is safe and 

effective among mid-adults, if they are exposed and susceptible to infection. However, the 

question being addressed is the additional health benefit and incremental cost-effectiveness of 

extending the HPV vaccine program through age 45 years or through another age between 27 

and 45 years.

Preliminary results from 3 health economic models were presented to ACIP during the October

2018 meeting. These models were the US HPV-Agent-based Dynamic model for Vaccination 

and Screening Evaluation (HPV-ADVISE) model, developed at Laval University working with 

CDC; the Simplified Model developed at CDC; and the Merck model. There were large 

differences in cost-effectiveness for mid-adult vaccination across models. After October, CDC 

requested input from another modeling group, the Cancer Intervention and Surveillance 

Modeling Network (CISNET). CISNET is a modeling network funded by the US National Cancer 

Institute (NCI).

Modelers and ACIP/CDC economic reviewers have been working to understand reasons for the

differences across models. As part of this effort, reviewers asked all modelers to include a set of 

results when using a set of standardized health economic parameters to facilitate comparisons.

Exploration of reasons for the large differences across the models have focused not only on 

health economic parameters, but also on other issues such as vaccination coverage. The model 

structures also have been reviewed. HPV epidemiology and natural history parameters could 

have a large impact on the models, so some aspects of these that might be contributing to 

differences in the model results were re-reviewed. Most HPV attributable cancers occur in midadults or older persons. The main question for current policy discussions and one of the issues 

that will impact the results from the modeling is, “How much disease is due to incident HPV 

infections that occur in mid-adults?”

Dr. Markowitz reviewed selected issues regarding natural history that would impact 

considerations in mid-adults. Understanding the burden of disease due to incident HPV infection 

in mid-adults requires consideration of many aspects of natural history, many of which were 

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discussed in June and October 2018. As a brief summary, incidence is highest in the late teens 

and early twenties. Over 90% of infections clear or become undetectable. New HPV infections 

do occur in mid-adults, with a new partner being the main risk factor. Epidemiology of HPV 

infection differs for males and females. There is some uncertainty about immunity after 

clearance of natural infection. This is thought to be generally low, but higher for females than 

males. Progression to cancer occurs over years to decades. Among HPV types that are 

oncogenic, some types are more oncogenic than others, particularly HPV 16. Less is known 

about the natural history of HPV and progression to cancer in males than in females [Rodriquez 

et al. JNCI 2010; Winer et al. CEBP 2011; Winer JID 2016; Beachler et al. JID 2016; Kahn et al. 

JNCI 2005; Giuliano et al. Int J Cancer 2015]. 

To review, the median age at diagnosis of 6 HPV-associated cancers in the US from 2011-2015

was shown. Among women, the median age at diagnosis of cervical cancer was age 49 years 

and for the other cancers, in the 60s. For men, the median age at diagnosis for all cancers was 

in late 50s and 60s. Again, the main question for the current policy discussion is, “How much of 

the disease is due to new HPV infections in mid-adults between the ages of 27 and 45 years old 

(versus how much is due to HPV acquired at younger ages)?”

[https://www.cdc.gov/cancer/hpv/statistics/age.htm].

Results have been shown to ACIP at past meetings from one of the CISNET modeling groups 

attempting to answer the question, “What proportion of cervical cancers is caused by HPV 

infections acquired at different ages?” The model estimate was that of women with cervical 

cancer, 50% acquired their causal infection by age 21 years and 75% by age 31. Other 

modeling teams are also working to estimate causal age at infection. Age at infection predicted 

by the model could account for some of the differences in cost-effectiveness across models.

Similar estimates have not been done for the other HPV-associated cancers.

The remainder of Dr. Markowitz’s talk focused on HPV infection and natural history in females at 

the cervical site, as much more is known about this natural history. She briefly reviewed 

infection, time from infection to cervical precancer, and from precancer to cervical cancer. This 

is a schematic showing the conceptual model of HPV infection leading to cervical cancer. This 

graphic is not to scale but shows approximately when these events occur:

Schiffman et al, Nature Reviews 2016

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Again, infection is highest in late teens and early 20s and then declines. Cervical precancers,

shown in green, are detected during and after the peak of infection, but the timing of precancer 

detection depends on cervical cancer screening because these lesions are asymptomatic. Most 

infections clear or become undetectable within 1-2 years. Many precancers also clear (30%-

40%). Precancer can progress to cancer after many years to decades.

Data have been presented to ACIP before from a variety of studies showing the decrease in 

prevalent and incident HPV infection with older age in females. Data from a study in Kaiser 

Permanente Northern California (KPNC) of the proportion of women with prevalent infection at 

enrollment and newly detected HPV infections at a follow-up among those who were negative at 

their first visit, show that both of these were significantly lower among older age groups.

Seroprevalence data also can provide information of incidence of infection, although 

seroprevalence is an imperfect measure of cumulative infection for HPV as not all individuals 

develop antibody after infection. Data from the National Health and Nutrition Examination 

Survey (NHANES) in the pre-vaccine era include any high risk 9vHPV type seroprevalence and 

any high risk 9vHPV type DNA prevalence by age group among females. In these data, DNA is 

highest at age 20-24 years and lower in older age groups. Seroprevalence increased from 11% 

in 14-19 year olds to 34% in 20–24 years, and is highest in the 30s. Seroprevalence did not 

change between early and late 30s. Seroprevalence was lower in older age groups as antibody 

from natural infection wanes and there is less new infection. Between the late teens and early 

20s, there was a 23 percentage point increase in seroprevalence and between late 20s and 

early 30s there was an 8 percentage point increase. These are cross-sectional data and age 

specific findings could be due to cohort effects. They do suggest new infection after the 20s but 

less than between the teens and 20s [National Health and Nutrition Examination Survey; CDC, 

unpublished data].

Breaking down the age groups into smaller categories (14-16, 17-19, 20-21 and 22-24 years), it 

is possible to see more clearly the rapid increase in high risk 9vHPV type seroprevalence in the 

late teens through early 20s from 8% in 14-16 year olds to 30% at age 20-21. These data also 

can be used to estimate cumulative infection. By age 21 years, an estimated 50% of females 

already had evidence of infection with at least one high-risk 9vHPV type. This calculation was 

based on the assumption that 60% of females develop antibody after infection, as has been 

shown in prospective studies. This estimate showing a large percent of females infected by the 

early 20s is consistent with the estimated age for causal infection from the model shown earlier

in the presentation [National Health and Nutrition Examination Survey; CDC, unpublished data].

To understand the burden of disease due to incident infection in mid-adults, it also would be 

helpful to know time for progression of incident infection to precancer and cancer. This might 

allow determination of age at which an infection occurred that caused that outcome. Time from 

infection to precancer has been estimated from the placebo arms of HPV vaccine clinical trials 

and from cohort studies. However, precancers are detected through screening, so duration of 

follow-up and intensity and methods of screening in these studies will impact findings. Time 

from precancer to cancer is more difficult to study as it is unethical to follow women 

prospectively with untreated high grade precancers, CIN3; however, it is likely to be decades 

based on the peak age of infection and cancer diagnosis. This also has been assessed in 

models. *An estimate from a statistical model also suggests a median of 23.5 years from 

precancer to screening-detected invasive cancer, with only 1.6% progressing within 10 years

[*Vink et al. AJE 2013].

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Dr. Markowitz showed data from three studies which looked at time from infection to CIN2+ 

detection. These studies had intensive screening ranging from every 4 months to every 6 

months. The median time from incident infection to precancer detection was 1-2 years1,2,3. In the 

Winer 2005 study, a simulation exercise was done to look at the impact of screening frequency 

on incidence, because cervical abnormities clear and would not be detected with less frequent 

screening. In terms of cumulative incidence under the assumption of different screening 

intervals after 48 months of follow-up, every 4-month screening yielded cumulative incidence of 

low grade cervical abnormalities of 29%, while with every 24-month screening the cumulative 

incidence was more than 2-fold lower 11.7% The simulation looked at low grade lesions, and a 

smaller impact of frequency would be expected for higher grade lesions but the direction of the 

effect would be similar1[

1Winer et al. JID 2005; 2

Insinga et al. CEPB 2011; 3Skinner et al. Int J 

Cancer 2016].

As just reviewed, time from incident infection to CIN2+ diagnosis estimated from studies can be 

short, but is impacted by duration of follow-up and screening. Age at CIN2+ diagnosis depends 

on age at clinical screening initiation, frequency, and methods. Importantly, a CIN2+ lesion can 

be present for years before it is detected because the time between CIN2+ and cancer is long.

Because of this, it is difficult to use age at CIN2+ diagnosis to estimate when infection occurred, 

particularly with the type of opportunistic screening available in most of the US.

Regarding the age distribution of cervical precancers in the US, data from CDC’s 5-site 

population-based surveillance, HPV Vaccine Impact Monitoring Project (HPV-IMPACT) from 

2008 were shown. These data were from before the impact of vaccination on precancers and 

before some of the recent changes in screening recommendations. CDC used these data to 

make projections for the US, and estimated that the annual number of CIN2+ cases in the US in 

2008 was 215,700 and the median age at diagnosis was 28 years [CDC, unpublished data; 

based on Gargano et al. CID 2018].

To illustrate the challenges of estimating age at infection from epidemiologic studies and 

surveillance data, Dr. Markowitz compared data from two different sources, the Atypical 

Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions 

(ASC-US/LSIL) Triage Study (ALTS) and the 5-Site HPV-IMPACT project. In the ALTS trial, 

which was a screening trial conducted among US women aged 18 years or older with every 6 

month screening, the median age of CIN3 detection was 23 years. In contrast, in the 5-site 

HPV-IMPACT surveillance project in which there is opportunistic “real life” screening, the 

median age at CIN3 detection was 30 years. Age at acquisition was likely similar, but the age at 

detection of precancer differed due to screening practices. This illustrates that it is difficult to use 

age at precancer detection to estimate age at causal infection.

Dr. Markowitz noted that while she did not provide an answer to the question about the amount 

of disease due to incident infections in mid-adults, she highlighted several issues related to the 

challenges in determining this. There is rapid acquisition of HPV in late teens and early 

twenties, and progression from incident infection to precancer can be within a few years. Over 

90% of infections clear and many of the precancers clear. Time from progression of precancer 

to cervical cancer is >20 years. Age at cervical precancer detection depends on screening age 

and frequency. Again, it is difficult to estimate age at causal infection from epidemiologic and 

surveillance data. Finally, less is known about the natural history of HPV at non-cervical sites 

and about progression from infection to cancer in males.

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There are challenges in estimating the burden of disease due to incident infections in mid-adults 

from empiric data. As mentioned at the beginning of this talk, health economic models have 

estimated this burden. However, exact model-based estimates of the burden of disease due to 

incident infection in mid-adults is also challenging. This is because model-based estimates 

depend on a variety of assumptions that are included in the models. This includes probability of 

infection, immunity after clearance of natural infection, sexual behavior and partner mixing, and 

progression and regression of precancer lesions. There will be further information about this in 

the health economic analyses in the next two presentations.

In closing, Dr. Markowitz briefly mentioned two other issues as an introduction to presentations 

later in this session: mid-adult vaccination recommendations and harmonization of HPV 

vaccination catch-up recommendations. Individual clinical decision-making for HPV vaccination 

in mid-adults is one of the options being considered by WG. This was presented to ACIP in 

October 2018. Acceptability and values about individual decision-making in mid-adults have 

been explored with some key stakeholders, which will be presented later in this session. In 

February 2018, before awareness of the application to FDA for the expanded age range, the 

ACIP WG was considering harmonization of the catch-up recommendations across genders. 

The WG has continued to focus on harmonization while considering mid-adult vaccination and 

members of the WG support harmonization. Results from surveys on harmonization conducted 

prior to consideration of mid-adult vaccination also will be presented later in this session.

HPV-ADVISE: Cost-Effectiveness of Extending 

HPV Vaccination Above Age 26 years in the US 

Marc Brisson, PhD

Professor, Université Laval

Dr. Brisson indicated that the study question they were given was, “From the health care sector 

perspective, what is the additional impact and cost-effectiveness of extending the established 

HPV vaccine program in the US to females aged 27-45 years and males aged 22-45 years? 

The scientific objective was to evaluate the additional population-level effectiveness and 

incremental cost-effectiveness of vaccinating females and males up to 45 years of age in the 

US against HPV versus the current recommendation. 

In order to do this, they used their model known as HPV-ADVISE. This model originally was 

developed to help inform HPV vaccination policy decisions in Canada, but has since been used 

and adapted for policy decisions in the US and more recently for global decisions in 

collaboration with the WHO. This is an individual-based transmission-dynamic model, so it is 

important to note that it includes herd immunity effects from vaccination. This model has 6 

integrated components: demographic, sexual behavior and HPV transmission, natural history of 

disease, vaccination, screening and treatment, and economics. The population is open and 

stable, and it includes individual women and men 10 to 100 years of age. HPV-ADVISE models 

18 genotypes individually, including the 9 types in the 9vHPV vaccine 

(6/11/16/18/31/33/45/52/58). The diseases modeled are anogenital warts (AGW), cervical 

cancers and cancers of the anus, oropharynx, penis, vagina, and vulva.

A very important element when developing a model is not only the programming, but also to 

confirm the model so that it reproduces actual epidemiological and behavioral data. The fitting 

process is very important. This is done through three steps. The first step was to find a minimum 

and maximum value for each of the parameters in the model, which are derived from the 

literature. The second step was to sample different combinations of these parameter values. 

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The third step was to identify multiple parameter sets that fit the US data. The US data that were 

fit include sexual and screening behavior that were stratified by gender and age; HPV 

prevalence stratified by HPV type, gender, age and sexual activity; incidence of anogenital 

warts, cervical lesions, cervical cancer and other HPV-related cancers stratified by HPV type, 

gender, and age. A total of 776 data points were fitted. There were 200,000 different 

combinations of parameters sampled from the prior parameter distributions. These were run 

through the model and 50 parameter sets were found that produced an acceptable fit to the 776 

pre-specified data target points. These sets were run through the model again with vaccination 

data to get effectiveness. Given that model fit is important, Dr. Brisson shared examples to 

illustrate model fit. For sexual behavior for women in the past 12 months aged 20-29 and 30-34, 

HPV prevalence in women for HPV-16/18 prevalence by age, AGW amongst females and 

males over age groups, and incidence of squamous cell carcinoma (SCC). The data also were 

fit to other HPV-associated cancers. Once the 50 data parameter sets are identified, the model 

is validated to real-world data (e.g., what is occurring in the US post-vaccination). The data were 

found to fit quite well, and will continue to be validated.

Once the model is validated, model predictions are done. For this question, the modelers 

wanted to focus on the experience in the US as much as possible. The changes in vaccination 

policies in the US were reproduced. In 2007, the policy was 3 doses of 4vHPV amongst females 

9 through 26 years of age. In 2011, the policy changed to gender-neutral vaccination with the 

addition of 4vHPV for men from 9 through 21 years of age. In 2015, there was a switch to 

9vHPV with 3 doses. In 2016, there was a switch for 9vHPV to a 2-dose strategy in girls and 

boys <15 years of age. In 2019, there is a new decision either to stick with the current 

recommendations or to extend HPV vaccination to mid-adults.

Historical vaccine coverage for the US also is reproduced in the model. For this, data were used 

from the National Immunization Survey-Teen (NIS-Teen) for individuals 13 through 17 years of 

age. Included in the model were the observed uptake rates and changes in uptake rates from 

2007 to 2016. There were no data for 18 year-olds, so the same uptake rates as 17 year-olds 

were assumed for 18 year-olds. From 2017 onward, uptake rates were assumed to be constant 

in the US at 2016 levels. For uptake rates amongst women and men above 18 years of age, 

uptake rates were provided by CDC HPV modelers. Coverage was validated to be reproduced 

extremely well.

There are 4 mid-adult vaccination scenarios for males and females. The first scenario is a 

harmonization scenario in which men up to 26 years of age are vaccinated. The other 3 

scenarios are vaccinating females and males up to 30 years of age, up to 40 years of age, and 

up to 45 years of age. Under these base case scenarios, vaccination uptake among adults not 

previously vaccinated is assumed to be 2.6% per year for women and 1.9% per year for men.

In terms of the economic analysis, it is conducted from the health care sector perspective. All 

direct medical costs are included. The outcome measure is cost per quality-adjusted life-year 

(QALY) gained. The future costs and benefits are discounted at 3% annually. The time horizon 

is 100 years beginning in 2007, the first full year of HPV vaccination in the US. The 9vHPV 

vaccination cost per dose was provided by CDC HPV modelers and for individuals ≤18 years is 

$205 (range $176-$235) and for those ≥19 years is $225 ($176-$235). Economic costs are 

included in the model for genital warts diagnosis and treatment, cervical cancer screening and 

treatment, and treatment of HPV-associated cancers. Costs found in the literature were included 

in the base case, but a sensitivity analysis also was performed using the maximum costs found 

in the literature and standardized costs provided by CDC were included as well in order to 

enable the comparison of all results to other modeling results.

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In terms of the results for effectiveness of HPV vaccination, the model predicts that over 100 

years with the current recommendation the US will prevent 13 million cases of CIN2/3; 32 

million cases of AGW; 653,000 cases of cervical cancer; and 269,000 cases of non-cervical 

HPV-associated cancers. With the current recommendation plus mid-adult vaccination up to 45 

years of age in females and males, there is very little difference. The model is predicting that 

there would be very small additional benefits of 56,000 additional cases of CIN2/3 prevented; 

124,000 additional cases of AGW prevented; 3000 additional cases of cervical cancer 

prevented; and 4000 additional cases of non-cervical HPV-associated cancers prevented.

Regarding why mid-adult vaccination is predicted to produce small additional reductions in 

burden compared to the current situation, the first reason pertains to the number of people 

vaccinated. The number of additional people vaccinated by extending vaccination to mid-adults 

is small compared to the enormous number of people who are vaccinated under the current 

program. The second reason is herd effects. The current vaccination program is predicted to 

provide substantial herd effects among unvaccinated adults older than 26 years. The incidence 

of infection and cancer among unvaccinated adults 26-45 years old will decline substantially due 

to herd effects. The third reason is the age of causal infection. In this model, a large proportion 

of cervical cancers are predicted to be caused by an HPV infection acquired before 26 years of 

age.

In a situation of no vaccination or screening, the model predicts that 50% of the cancers are 

caused by an infection occurring before the age of 20. This is very much in line with the results 

that Dr. Markowitz presented earlier from the Harvard group. In addition, about 80% of all of the 

cancers are due to infections that were acquired before 25-26 years of age. Thus, there is 

limited potential for additional gain by vaccinating mid-adults.

With respect to how this translates into cost-effectiveness, the first comparison to assess is the 

current recommendation compared to no vaccination. This model suggests that the current 

strategy is highly cost-saving. Various mid-adult scenarios were then compared to the current 

recommendations. The first scenario assessed was harmonization in which females and males 

are vaccinated up to 26 years of age. It was not possible to calculate a case-effectiveness ratio 

in this case, because it was not possible to identify significance gains in this scenario. For midadult vaccination up to 30 years of age, the medium cost-effectiveness ratio was $830,000. For 

the scenario in which females and males are vaccinated up to 45 years of age, the costeffectiveness ratio jumped up to $1.5 million. It is also important to note that the results are 

quite variable, so there is a lot of uncertainty around the estimates. The ranges shown reflect 

the 90% uncertainty interval. This is the 5th and 95th percentile of predictions generated by the 

50 best-fitting parameter sets. This could be the analogue to a confidence interval, and they are 

quite wide.

It was identified that the driver for the results being so variable was likely to be the variability in 

natural immunity parameters. Two families of parameter sets were found: the 22 parameter sets 

that had faster progression from infection to lesions and lower natural immunity, and the 28 

parameter sets that had slower progression and higher natural immunity. In the “faster 

progression” parameter sets, the average time from an infection to a lesion was about 2 years. 

In terms of lower natural immunity, these scenarios were predicting that natural immunity 

following clearance in females was 35%, so the probability of developing natural immunity was 

less than 35%. Conversely, in the “slower progression” parameter sets, the average time from 

infection to lesions was 30 months and the probability of developing natural immunity after 

clearance was 35%. This stratification of parameter sets by natural history parameters did make 

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a big difference. For example, the cost-effectiveness for vaccinating females and males up to 30 

years of age, the median result for the 50 parameter sets was $830,000. However, when using 

the family of parameter sets with faster progression, the cost-effectiveness ratio was then 

$404,000; whereas, for the slower progressors, the cost-effectiveness ratio was $2.3 million.

In the sensitivity analyses for vaccination parameters, two parameters stood out more than 

others. In the scenario of vaccinating females and males up to 30 years of age, the first 

parameter that had a major impact on the results was historical vaccination coverage. With 

lower historical vaccination coverage, the cost-effectiveness ratios were much lower. Just 

assuming lower historical vaccination coverage reduced the median cost-effectiveness ratio 

from $830,000/QALY gained to $336,000/QALY gained. The other parameter that had a big 

influence on the model was vaccine efficacy (VE). If low VE was assumed, cost-effectiveness 

was better. Both scenarios of low historical vaccination coverage or low VE make it such that 

the current program has lower herd effects, which results in less reduction in HPV in the men 

and women who are 26 years of age and older. The absolute potential reduction in HPV in 

these mid-adults will be bigger. That is, there will be bigger potential for reductions in HPV in 

mid-adults if there are lower herd effects of the historical vaccination program. Sensitivity 

analyses also were performed to assess whether varying the economic parameters would have 

an impact on the predictions, and they did not significant impact the model predictions.

In terms of the strengths of the analyses, HPV-ADVISE is calibrated to highly stratified US data. 

The model is validated with post-vaccination US data. The predictions are consistent with agespecific post-vaccination HPV infection and AGW diagnosis data from the US.1 HPV-ADVISE 

has also been validated to post-vaccination data in Australia.2 Predictions are made using 50 

parameter sets, which captures uncertainty in the natural history of HPV infection and related 

diseases, and variability in sexual behavior data. This results in wide uncertainty intervals, 

reflecting that results are highly sensitive to natural history assumptions and lack of data among 

mid-adults. Sensitivity analyses were performed on key parameters [1Drolet IPVC 2018; 2Drolet 

JID 2018].

Regarding the limitations of examining mid-adult vaccination, long-term herd effects of 

vaccinating younger age cohorts on mid-adult women and men remains uncertain. If HPVADVISE overestimates herd effects of the current program, the results may overestimate the 

cost-effectiveness ratios of vaccinating mid-adult men and women. However, the model’s 

consistency with post-vaccination data suggests that the model reproduces short-term postvaccination herd effects. Time to lesions and level of natural immunity after infection remain 

uncertain. Model predictions are very sensitive to these natural history parameters. The relative 

progression of a re-infection or new infection in mid-adults versus younger adults is unknown. 

HPV-ADVISE assumes that progression is independent of age. However, it has been suggested 

that a proportion of re-detection is due to deposition1, and that new infections later in life have a 

smaller risk of progressing to cervical cancer.2,3 If this is the case, mid-adult vaccination would 

produce lower benefits and higher cost-effectiveness ratios. Screening recommendations are 

changing in the US. If changes to screening result in more effective cervical cancer prevention, 

mid-adult vaccination would produce lower benefits and higher cost-effectiveness ratios 

[

1Malagon JID 2017; 2Plummer Int J Cancer 2012; 3Rodrigez JNCI 2010].

In summary, the current HPV vaccination program is predicted to reduce the burden of HPVrelated disease substantially (e.g., 82% reduction in anogenital wart diagnoses and 59% of 

cervical cancer cases over 100 years), and is likely cost-saving versus no vaccination. 

Extending vaccination to 45-year-old females and males is predicted to produce small additional 

reductions in HPV burden of disease (e.g., additional 0.2-0.4 percentage point reduction in 

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anogenital warts diagnoses and cervical cancer cases). This results in cost-effectiveness ratios 

of ≥$360,000 per QALY-gained in 95% of model simulations under the base case assumptions, 

with a median of $1.5 million. Finally, the cost-effectiveness of mid-adult vaccination is highly 

sensitive to natural history assumptions and historical vaccination coverage.

Impact and Economic Analyses

Harrell Chesson, PhD

Health Economist

Centers for Disease Control and Prevention

Dr. Chesson provided an overview of all of the modeling results, including those just presented 

by Dr. Brisson. The ACIP review process is ongoing for four of the five health economics 

models presented during this session. The ACIP review is completed for the HPV-ADVISE 

model, but the results presented from the other models should be considered preliminary. 

During the October 2018 ACIP meeting, the 3 health economics models available of 9vHPV 

vaccination were reviewed (HPV-ADVISE, Simplified, Merck). It was shown that there were 

notable differences in the cost-effectiveness estimates across the models.

Since then, some progress has been made in examining these issues. The HPV-ADVISE 

estimates have been finalized. The Simplified model has been adjusted to better approximate 

scenarios in which there is re-infection. The Merck model has been recalibrated to fit prevaccine era HPV prevalence data and now uses NIS-Teen data for historical vaccine coverage 

assumptions, as in the other models. As Dr. Markowitz mentioned, results from two CISNET 

models are now available and there is a better understanding of some of the reasons for 

differences across models.

The 5 9vHPV models now available include:

❑

❑

❑

❑

HPV-ADVISE model (Laval University/CDC)

Simplified model (CDC)

Merck Model

Two CISNET models: 1) Harvard; 2) Policy1-Cervix (Cancer Council New South Wales, 

CCNSW)

All 5 of these models are dynamic; that is, they include herd effects. They also include a wide 

range of health outcomes that can be prevented through vaccination, such as cervical 

precancers and cancer, other HPV-associated cancers (e.g., anal, vaginal, vulvar, penile, 

oropharyngeal), and genital warts. All of the models apply recently published estimates of the 

medical costs for HPV-associated cancers. The models all exclude productivity costs and 

examine a relatively long time horizon of 100 years or more to capture all of the benefits of HPV 

vaccination.

In terms of selected model attributes, 3 of the 5 models (HPV-ADVISE, CISNET Harvard, 

CISNET Policy1-Cervix) are individual-based, which means the models keep track of individuals 

in the population. The other 2 models (Simplified, Merck) are compartmental, which means that 

they keep track of groups of people in the population. All of the models, except the Simplified 

model, include historical vaccination coverage. In terms of model calibration, HPV-ADVISE uses 

the 50 best-fitting parameter sets for analyses. The Merck model and the 2 CISNET models use 

a single best-fitting parameter set.

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All of the models except the Simplified model assume that the vaccine will protect against 

reinfection for those who are vaccinated after clearance. Regarding cervical cancer screening 

assumptions, HPV-ADVISE and the Merck model approximate real-world cervical cancer 

screening. The CISNET models in the base case assume perfect compliance to cervical cancer 

screening guidelines, but also examine the impact of applying real-world screening scenarios in 

the sensitivity analyses. The vaccine uptake among mid-adults is similar for all of the models. 

The only difference really is that Merck allows for the possibility of incomplete vaccination 

series, given that some adults might receive 1 or 2 doses rather than all 3 doses. As described 

in the previous presentation, the models were calibrated to fit the data. One of the parameter 

values that is fit during the calibration process has to do with natural immunity. In all but the 

Simplified model, there are assumptions regarding natural immunity.

Moving on to some of the results across the models, the median age of first acquisition with at 

least one high risk 9vHPV type (16/18/31/33/45/52/58) is closer to 20 to 21 years in the HPVADVISE and Simplified model, and in the Merck model is around 25-26 years of age. Based on 

the NHANES seroprevalence data presented earlier in the session by Dr. Markowitz, by age 20-

21 years an estimated >50% of females already had evidence of infection with >1 high risk 

9vHPV type assuming that 60% of females develop antibody after infection. As far as the costeffectiveness of the current HPV vaccination strategy, in the HPV-ADVISE model the current 

program is estimated to be cost-saving. This is a very consistent result with the other models, 

which find a very low cost per QALY for the current vaccine program versus no vaccination.

Before showing the cost-effectiveness results for mid-adult vaccination, Dr. Chesson indicated 

that he would be presenting 2 main measures. The first is the cost-effectiveness of adding midadult vaccination through age 30 years versus the current program, and the second is for 

extending mid-adult vaccination through age 45 years versus the current program. Though he 

did not present it during this session, Dr. Chesson indicated that modelers have examined a 

wide range of other strategies, such as vaccination to age 35 years or 40 years. They also have 

examined the incremental cost-effectiveness ratios, such as the cost-effectiveness of a midadult vaccination program through age 35 years versus age 30 years.

In terms of the base case results from the models of mid-adult vaccination through 30 years of 

age, the median from the 50 parameter sets in the HPV-ADVISE model was about $830,000. 

The estimates in the other models ranged from about $100,000 in the Merck model to over 

$600,000 in CISNET Harvard model. For vaccination through 45 years of age, the median in the 

HPV-ADVISE model was about $1.5 million. The estimates in the other models ranged from 

about $150,000 in the Merck model to about $400,000 in the Simplified and CISNET Harvard 

model.

A distinctive feature of the CISNET results is that the cost per QALY is lower for mid-adults 

through age 45 than it is for mid-adults through age 30. This was a somewhat unexpected result 

because typically, the cost per QALY gained by HPV vaccination is estimated to increase when 

the age at vaccination is increased. The main reason for the CISNET result is thought to be that 

vaccinating younger people is having herd effects on unvaccinated mid-adults. Thinking of herd 

effects as a wave moving from the young people to the mid-adults, that wave will hit the younger 

mid-adults before it hits the older mid-adults. Therefore, there is more room for the vaccine to 

have an effect on the older mid-adults up to age 45 rather than the younger mid-adults under 

age 30.

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Several factors have been assessed to try to determine what could account for the differences 

across the models. In terms of health economic parameters, issues such as vaccination costs, 

medical treatment costs, and QALY assumptions could have an impact. ACIP reviewers asked 

the modelers to include a set of results when using a standardized list of health economic 

parameters. It is known that historical and future vaccination coverage assumptions can affect 

these estimates. Model structure and assumptions regarding sexual behavior and HPV 

transmission dynamics; natural history of HPV infection; and cervical cancer screening, 

diagnosis, and treatment also can affect the estimates.

It is not clear yet whether the differences in results can be explained by differences in health 

economic assumptions (e.g., vaccination costs, medical treatment costs, QALY impacts), given 

that these analyses are not yet complete. The results are anticipated to be available before the 

next ACIP meeting. Regarding whether historical vaccination coverage assumptions matter, all 

of the models include historical vaccination coverage, except the Simplified model. Instead of 

examining whether mid-adult vaccination should be added to an ongoing program that has been 

in existence for over a decade, the Simplified model asked what the cost-effectiveness would be 

if HPV vaccination was started today that included mid-adult vaccination in the program. 

Accounting for the historical vaccine coverage does matter. When lower historical coverage or 

no historical coverage is assumed, the cost per QALY gained by mid-adult vaccination is much 

lower. With lower historical vaccination coverage, there are less herd effects of the current 

vaccination program on mid-adults, and thus more potential benefits of mid-adult vaccination. In 

a sensitivity analysis, the HPV-ADVISE and Merck models eliminated the historic vaccination 

program to make them compatible with the Simplified model assumptions. In doing so, the 

Simplified model result and the HPV-ADVISE result are much closer together than they were 

before.

With respect to what can be learned by exploring multiple parameter sets, the HPV-ADVISE 

examines the 50 best-fitting parameter sets and the Merck and CISNET models use a single 

best-fitting parameter set. Using multiple parameter sets helps to understand how sensitive the 

results are to key assumptions regarding natural history of HPV infection, HPV transmission 

dynamics (sexual behavior, transmission, et cetera), and so forth. As Dr. Markowitz pointed out 

in her presentation, these assumptions are subject to considerable uncertainty. Across the 50 

parameter sets, the cost per QALY by mid-adult vaccination through age 45 years ranged from 

a median of about $1.4 billion to a low of about $360,000 to undefined.

Regarding the effect of assuming perfect screening compliance, the CISNET models assume 

perfect cervical cancer screening compliance in their base case analysis and real-world 

screening in a sensitivity analysis. The HPV-ADVISE and Merck models simulate real-world 

screening. The CISNET estimates of the cost per QALY gained by mid-adult vaccination are 

much lower when assuming real-world screening versus perfect screening. That is because 

there is more potential benefit in these scenarios for the vaccine to prevent cervical cancer. The 

estimates for the CISNET models when assuming real-world screening rather than their base 

case assumption of perfect screening are $363,800 (Harvard) and $199,300 (Policy1-Cervix).

The following tables summarize what the studies show about the general range of cost per 

QALY estimates for mid-adult vaccination through age 30 years and through age 45 years in 

terms of whether the estimated cost per QALY gained is below the following values: $100K, 

$150K, $200K, $300K, $400K and $500K: 

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There is still agreement across most of the models that the cost per QALY gained through midadult vaccination through age 45 years is not less than $300,000.

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To summarize the cost-effectiveness estimates from the models, the current US HPV 

vaccination program has a very favorable cost-effectiveness profile. The program is likely costsaving or at least a very low cost of <$10,000 per QALY gained. All models find that mid-adult 

vaccination is relatively less cost-effective than the current program. However, because of the 

uncertainties in the natural history of HPV, transmission dynamics, and other factors it is not 

possible to provide a single precise estimate of the cost-effectiveness of mid-adult vaccination. 

It is only possible to show the ranges across the models. For mid-adult vaccination through age 

30 years, the cost per QALY gained exceeds $200,000 in 3 of the 5 available models; $300,000 

in 3 of 4 of the models that take into account historical vaccination coverage; and $800,000 in 

the median of the HPV-ADVISE model. Similarly, for mid-adult vaccination through age 45 

years, the cost per QALY gained exceeds $300,000 in 4 of the 5 available models; $400,000 in 

3 of the 5 available models; and $1.4 million in the median of the HPV-ADVISE model.

The next steps are to complete the ACIP reviews that are ongoing for 4 of the 5 models. 

Collaboration will continue with the modelers to understand the important differences in model 

structures and assumptions that drive the results, including completing a “standardized health 

economic assumptions” scenario; finalizing the ACIP economics review process; and providing 

more details to the HPV WG. Preparations will be made for the June 2019 ACIP meeting and to 

address any issues raised during this session.

Discussion Points

Dr. Elbasha (Health Economist, Merck) indicated that he has led the development of the Merck 

HPV model over the last 16 years or so, and expressed appreciation for the opportunity to share 

Merck’s perspective on the public health impact on the cost-effectiveness of expanding 

vaccination to 45 years of age. According to analyses from the Merck model, expanding 

vaccination avoids significant disease and deaths of approximately 26,400 cancer cases, 8800 

cancer deaths, and 1.6 million cases of AGW and cervical lesions at an incremental costeffectiveness ratio (ICER) of less than $150,000 per QALY. Several other policy options for 

expanding the program were not highlighted, but have lower ICERs. These include limiting the 

duration of the program to 10 years, expanding only to women, or expanding the program to 

only age 35 for both men and women. The findings of the results from all of these models is not 

aligned and requires further investigation, as mentioned by Dr. Chesson. In the younger cohort 

in the current recommendation, these models have aligned. It is unusual for models to have 

wide variation in the results like this. Merck thinks it is important for all modeling groups to work 

together to fully understand what might be driving the results and the differences in the results. 

This would include sharing equations, inputs, and other technical details of the models. Merck 

would welcome further review by the CDC team, any advice from the ACIP WG and ACIP, and 

any opportunities to work with other modeling groups, including participating in a face-to-face 

meeting. This would greatly help decision-makers to accurately assess the public health impact 

and the true economic value of expanding HPV vaccination to 45 years of age.

Dr. Talbot observed that this would be a permissive recommendation for someone who is newly 

at risk or who has a changed risk. None of these models evaluated by risk, but she wondered 

whether that would be feasible to do. While she could not imagine that a 35-year old in a 

committed relationship suddenly being at risk, but a 35-year old who is divorced and out 

exploring would be at a completely different risk and would have a different cost per QALY 

gained.

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Dr. Markowitz indicated that consistent with Dr. Talbot’s observation, the WG is considering the 

option of individual decision-making. They have been spending a lot of time looking at the 

modeling and hope to be able to address the issue of who would benefit—low risk people who 

are just entering or re-entering sexual activity, or high risk people who are continuing high risk 

sexual activity. While this is another full project for the modelers, it is a very good question.

Dr. Ezeanolue observed that herd effects seemed to be an important factor in all of the 

modeling shown. Based on the 10-year history of vaccine uptake, he wondered whether vaccine 

uptake is anticipated to increase, decrease, or stay the same. He also wondered what the 

thoughts were on making a recommendation for 10 years and then stopping. This is an 

important option that should be considered, because the goal is catch-up such that by the end 

of the 10 years a lot of the people who have received vaccination will have aged into this age 

group. He liked the suggestion for all of the modelers to get together, and thought it would be 

beneficial for ACIP to have more information before making a decision, including modeling 

projected outcomes from a 10-year catch-up strategy.

Dr. Markowitz responded that even if current uptake remains consistent, eventually coverage 

will increase as vaccinated people age into the older age groups. The models do take that into 

account. With higher coverage, there will be higher herd immunity. The models are assuming 

current coverage based on NIS-Teen, which levels off at a certain point.

Dr. Brisson added that their assumption is that at some point, an equilibrium will be reached in 

vaccination coverage of just under 80%. With this level of vaccine coverage, substantial herd 

effects would be expected. Data from other countries, that have reached very high coverage of 

approximately 80%, indicate important herd effects occur in the older age groups. There is good 

literature based on real-world data showing that herd effects are occurring in men and older 

women who are not vaccinated. They have performed some additional analyses on the wave of 

herd effects, and found that a short-term catch-up strategy among mid-adults would be more 

cost-effective than a permanent catch-up strategy, because the main gains predicted by the 

model are in the first cohorts vaccinated before all of the herd effects are realized. It is a very 

good idea to consider whether a short-term mid-adult vaccination strategy would be worthwhile, 

cost-effective, and beneficial. As Dr. Elbasha mentioned, another strategy would be to vaccinate 

only mid-adult females. Though not presented during this session, modelers at Laval have 

analyzed this strategy and found it to be more cost-effective. He thought it would be interesting 

to examine the potential outcomes of a 10-year catch-up strategy. Dr. Brisson is involved with 

WHO in writing a paper regarding how to do comparative modeling. There is a systematic 

approach that can be taken that it is better than sitting in a room debating who is right and who 

is wrong, which is not going to change things. A systematic approach to comparing the models 

is a better way forward.

Dr. Lee said the strategy suggested was a precision public health approach, which is to optimize 

the health benefits for the population but target the recommendations accordingly. The 

challenge is with implementation and de-implementation of programs, which is part of the EtR 

Framework. The same challenges are arising with the pneumococcal recommendations.

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HPV Vaccination in Mid-Adults: Patient Values and Acceptability

Nancy McClung, PhD, RN 

Epidemic Intelligence Service Officer 

Division of Viral Disease

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. McClung reminded everyone that patient values and acceptability are part of the EtR used 

by ACIP, and that the objective of this presentation was to review what is known about patient 

values and acceptability for HPV vaccine in mid-adults 27-45 years of age among women, men, 

and MSM. In terms of methods, a literature search was conducted using PubMed for “HPV 

vaccine acceptability.” The search included US studies with information reported in mid-adult 

women or men and if greater than 50% of the sample was age 26 years or older. After reviewing 

336 results, 10 papers were selected for inclusion. Of these, 6 papers were in women, 2 in men, 

and 2 in MSM. The studies were ordered by the year data were collected, which is shown in 

parenthesis after each study.

Regarding values and acceptability in mid-adult women, the most recent study by Dempsey 

(2014) assessed wanting to receive the HPV vaccine if a provider had it available and 

recommended it. Of the women, 50% reported definitely or probably wanting it. The Liau (2009) 

study assessed, on a scale of 0 to 100, willingness to be vaccinated if the vaccine was free. The 

mean score was 64. The Weiss study (2008) assessed relevance of the HPV vaccine. Of the 

respondents, 67% reported that the HPV vaccine was relevant to them. Of those, 71% reported 

likely to get the vaccine if available. The Fazekas study (2006) found that 66% of respondents 

were likely to get the vaccine if it was free. The Hopenhayen study (2005) and Slomovitz study 

(2004) assessed values and acceptability prior to routine recommendation in the US. In the first, 

85% reported that if an HPV vaccine was approved to prevent cervical cancer, they would want 

to get vaccinated. The second found that 77% would accept the HPV vaccine if it worked at any 

age. Common reasons mid-adult women reported not valuing or intending to receive the HPV 

vaccine include being married, being in a monogamous relationship, perceived low risk for HPV 

infection, lack of sexual activity, and unknown adverse side effects.

In terms of values and acceptability in mid-adult men, all of the studies in mid-adult men were 

conducted prior to a routine vaccine recommendation for men. The most recent study by Daley 

(2007-2009) included men in a longitudinal HPV study and reported, by race/ethnicity, likelihood 

to get the vaccine if safe and effective for males. Of the men, 74% to 94% reported being likely 

or very likely to be vaccinated. The study by Reiter (2009) assessed willingness to get the 

vaccine if it was approved for males, with 37% of men reporting that they would receive the 

vaccine. The study by Sanchez (2008) among MSM assessed willingness to receive the 

vaccine, with 86% of MSM reporting that they would receive the vaccine. The study by Reiter 

(2009) among MSM assessed willingness to receive the vaccine if it was approved for males; 

74% reported that they would receive the vaccine. Common reasons mid-adult men reported

not valuing or intending to receive the HPV vaccine for heterosexual men included being 

married or living with a partner or having less than 5 lifetime sex partners. The reason mid-adult 

gay or bisexual men reported not valuing or intending to receive the HPV vaccine gay or 

bisexual men was having less than 5 lifetime partners.

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There are a few limitations to the studies in this review. First, it is important to note that all 

studies were conducted prior to licensure through age 45 years. Thus, the values and 

acceptability reported in these studies do not directly relate to the expanded age licensure, but 

rather are based on a hypothetical situation. In women, the most recent data were collected 

more than 5 years ago. In men, all of the studies occurred before a routine HPV vaccine 

recommendation was made for men.

In conclusion, overall value and acceptability of HPV vaccination was moderate. Valuing or 

intending to receive the HPV vaccine was reported by at least 50% of the sample in all studies 

but one. Willingness to receive the vaccine was high in both studies among MSM. However, 

HPV vaccination was not valued by all respondents. The most common reason the vaccine was 

not valued was low perceived risk for HPV; that is, being married, in a monogamous 

relationship, or having few sex partners. 

Program and Vaccine Provider Surveys

Elissa Meites, MD, MPH

Medical Epidemiologist, Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Meites presented the results of program and vaccine provider surveys regarding mid-adult 

HPV vaccination. The EtR Framework includes consideration of acceptability of mid-adult HPV 

vaccination to key stakeholders. In addition to patients, discussed in the previous presentation 

by Dr. McClung, key stakeholders also include immunization programs and vaccine providers 

such as physicians. This presentation summarizes data from 4 different surveys on 2 issues 

related to adult HPV vaccination: 1) harmonization of upper age catch-up recommendations 

across genders, including surveys of programs and primary care physicians; and 2) individual 

decision-making, including surveys of programs related to mid-adult HPV vaccination, and 

primary care physicians on category B recommendations.

The first survey is a harmonization survey of immunization programs, conducted in January and 

February 2018 by the Association of Immunization Managers (AIM). Among 64 immunization 

programs, the response rate was 80%. Almost three-quarters of these programs purchased 

adult HPV vaccine through the CDC contract and also provided adult HPV vaccine to any health 

department clinic. This survey found that 96% of programs were aware that catch-up 

recommendations currently differ between males and females, and 59% stated that the current 

recommendations cause challenges or confusion. Almost all, 98% of programs, were in favor of 

harmonizing the recommended age for catch-up vaccination to include everyone through age 26 

years. Reasons why 50 of 51 programs were in favor of harmonization were as follows:

❑

❑

❑

❑

❑

❑

❑

Easier to implement (46, 90.2%)

Easier to explain to patients (44, 86.3%)

Would simplify health department recommendations and guidelines (42, 82.4%)

Easier to explain to providers (42, 82.4%)

Facilitate reaching high-risk populations (42, 82.4%)

Create equity between genders (39, 76.5%)

Reduce burden on health care providers (38, 74.5%)

[Unpublished data, Association of Immunization Managers (AIM), January–February 2018].

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A second harmonization survey of primary care physicians was conducted in January and 

February 2018 by the University of Colorado. Among 1,383 physicians, including about equal 

numbers of pediatricians, family physicians, and internal medicine physicians, the response rate 

was 59%. Here, only about 58% said they were aware of the difference in catch-up 

recommendations for males and females, and about a quarter (27%) said the current 

recommendations have caused challenges or confusion in their practices. But again, most 

(93%) were in favor of harmonization across genders. 

Reasons why 713 physicians favored harmonization were: 

❑

❑

❑

❑

❑

❑

❑

❑

❑

Reasons why 53 physicians did not favor harmonization were: 

Simplify the vaccination schedule (693, 99.3%)

Easier to implement (668, 97.0%)

Easier to explain to patients (664, 96.1%)

Facilitate reaching high-risk populations (605, 87.9%)

Reduce burden on health care providers (544, 80.1%)

Create equity between genders (412, 60.7%)

I don’t have a problem with the current recommendation (44, 91.7%) 

Vaccination is less cost-effective in older age groups (24, 53.3%)

I don’t think HPV vaccine should be administered to all males in this age group (23, 52.3%) 

[Unpublished data, Children’s Outcomes Research, University of Colorado, 2018]

Regarding the topic of individual decision-making for mid-adult HPV vaccination, the third 

survey of immunization programs also was conducted by AIM in January and February 2019. Of 

64 immunization programs, the response rate was 64%. The first question was, “If there is a 

recommendation for individual decision making for vaccination of mid-adults, how challenging 

would it be for your immunization program to communicate the recommendation to vaccine 

providers in your jurisdiction?” Of responding programs, 5 (11%) responded that it would be 

very challenging, 22 (49%) said somewhat challenging, and 16 (36%) said not challenging. The 

second question was, “If there is a recommendation for individual decision-making for 

vaccination of mid-adults, in your opinion and/or experience, how easy would it be for vaccine 

providers to determine patients in this age group who might benefit from vaccination?” Of 

responding programs, 5 (11%) responded that it would be easy, 14 (31%) said somewhat easy, 

and 19 (42%) said not easy. The third question was, “Do you anticipate any challenges to 

implementing such a recommendation?” Of responding programs, 31 (69%) said yes, and 14 

(31%) said no.

Some of the stated reasons why programs said individual decision making could be 

implemented were:

❑

❑

❑

❑

FDA already announced licensure of HPV vaccine through age 45 years 

Some immunization programs (not all) already have mechanisms in place to communicate 

new recommendations to adult immunization providers in their jurisdiction 

Easy to identify patients in the mid-adult age range using electronic health records (EHRs)

Identifying patients most likely to benefit might be easier for certain provider types, for 

example, clinicians who are already regularly vaccinating adults and assessing sexual 

history 

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Some of the stated reasons why programs said individual decision making could be challenging 

were:

❑ Primary focus of the HPV program is to vaccinate children and adolescents; expanding the 

age range could distract from this main goal 

❑ HPV vaccine messaging should remain focused on disease prevention (cancer), not 

transmission (sex); individual decision making could undermine communication of disease 

prevention messages for adolescents by reinforcing transmission messages for adults

❑ Immunization Information Systems (IIS) are unable to forecast for individual decision 

making, and would have to prompt all or none in the mid-adult age group to have a 

conversation

❑ Not all vaccine providers assess sexual history and not all patients disclose

❑ Might be too complex, confusing, or time-consuming for vaccine providers

❑ Little funding for adult vaccine programs; 317 funds are already spread thin

[Unpublished data, Association of Immunization Managers (AIM), January–February 2019].

Although a provider survey on individual decision-making has not been conducted for HPV 

vaccination, the WG did review results of a 2016 survey about what was then called “Category 

B” recommendations for meningitis B vaccine (MenB), conducted by the University of Colorado. 

Among 916 primary care physicians, the response rate was 72%, including 374 pediatricians 

and 286 family physicians. Overall, 589 (89%) needed additional guidance on how to tell 

patients what a Category B recommendation is; 458 (69%) felt that vaccines with a Category B 

recommendation require more discussion with patients than “Category A” routine 

recommendations, and 299 (45%) did not know that private insurance companies routinely 

cover Category B vaccination recommendations. The WG noted that current terminology, using 

“individual decision making” instead of “Category B,” might reduce some of this confusion, and 

acknowledges the importance of clear guidance with this type of recommendation [Kempe et al, 

Knowledge and Attitudes Regarding Category B ACIP Recommendations, Acad Pediatr. 2018;18: 763-

768].

In summary, harmonization of upper age for HPV vaccine catch-up recommendations across 

genders would likely be acceptable to key stakeholders, including 98% of immunization 

programs, and 93% of primary care physicians. As a reminder, these surveys were conducted 

before HPV vaccine was licensed above age 26, but interest in harmonization across genders 

likely still applies. Also, individual decision-making for persons older than the routine catch-up 

age group through age 45 years might be acceptable to key stakeholders. The majority of 

immunization programs anticipated challenges communicating such a recommendation. Almost 

half thought it would be easy or somewhat easy for providers to determine who might benefit 

from vaccination. About a third anticipated no challenges with implementation. These data will 

be incorporated into the EtR Framework on acceptability of mid-adult HPV vaccination to key 

stakeholders. 

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Recommendation Options 

Lauri Markowitz, MD 

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

To end this session, Dr. Markowitz briefly reviewed the WG’s considerations for mid-adult HPV 

vaccination. As a reminder, the current recommendations for HPV vaccination in the US are as 

follows: routine vaccination at age 11 or 12 years; catch-up vaccination for females through age 

26 years and males through age 21 years, as well as certain populations (e.g., MSM, 

transgender persons, and persons with certain immunocompromising conditions) through age 

26 years; and males aged 22 through 26 years may be vaccinated [MMWR 2014;63 (RR05), 

MMWR 2015;64:300-4, MMWR 2016; 65:2105-8].

The WG is still reviewing results from health economic analyses as well as other data related to 

this policy question. Several policy options have been discussed, which Dr. Markowitz

summarized in terms of a majority and minority opinion. The majority opinion, which is favored 

by a large majority of the WG members is for harmonization of the upper age for catch-up 

across genders. This could be at the current age or another age (e.g., 26 or 30 years). For 

those older than the catch-up age, individual clinical decision-making through age 45 years was 

favored. The minority opinion was the same in terms of catch-up vaccination; however, there 

would be no recommendation for vaccination of those older than the harmonized catch-up age.

Concerns among WG members favoring no recommendation above a harmonized catch-up age 

are that there are few benefits for vaccination in the older age group. It would be a diversion of 

focus from the adolescent vaccination program. A few members thought there would be 

potential harms to the HPV vaccination program due to temporally associated AEs in this age 

group. The WG also discussed the current global HPV vaccine supply situation, which was 

discussed with ACIP in October 2018. This was important for a few WG members.

Of note, no WG members are in favor of a catch-up recommendation through 45 years of age. If 

individual clinical decision-making is recommended in some age groups, the WG did understand 

that there would be challenges about what guidance to provide, how to communicate who might 

benefit, and how to communicate the lower effectiveness in this age group. All of these would 

have to be addressed, which the WG acknowledges.

The next steps are for the WG to continue to review results from health economic modeling and 

other related data, complete the EtR Framework, and prepare for a vote in June 2019.

Discussion Points

Dr. Hunter observed that the ability to implement a cohort-based/age-based recommendation 

that would be not individually decision-making but would be a routine recommendation, could be 

conceived of as cohort-based by year of birth similar to how HepC testing is done. Everybody is 

tested for HepC for a birth cohort from 1945-1965. If catch-up was recommended through age 

35 for a current cohort, those years of birth would be used on top of a general individual

decision-making recommendation that would persist ongoing. Once individuals aged out of that 

cohort, then people would get the previous age-based recommendation. While he was not 

saying this should be done or was the right thing to do, it could be done. Further cost analyses 

could help determine whether that would make sense to do.

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Dr. Ezeanolue pointed out that individual decision-making is automatic, even now. If someone 

wants a vaccine, they can pay for it and get it. He requested clarity about how what they were 

discussing differed from what exists now.

Dr. Cohn indicated that if ACIP recommends a vaccine for individual clinical decision-making, 

that means that the vaccine goes on the immunization schedule for that age group in a different 

color than the color for routine vaccination. That cues providers to thinking about considering it 

for their patients, and provides coverage through the ACA. Payment is one of the key 

differences, and providers use the schedule and programs consider it as part of their decisionmaking when it is included on the schedule versus when it is not included.

Dr. Szilagyi clarified that if ACIP makes an individual clinical decision-making recommendation, 

they are recommending that clinics go through the process of making individual decision-making 

and guidance would follow. Making no recommendation means ACIP is silent on it. It is a 

different level of thought process. It was the WG’s understanding that if ACIP does not make a 

recommendation, insurance will not cover it.

Dr. Ault pointed out that in women’s health, there are a fair number of examples of individual 

clinical decision making (e.g., breast cancer screening, contraception, screening aneuploidy 

during pregnancy, et cetera).

Dr. Moore thought one analogy to use to help people think about individual decision-making with 

HPV vaccine in this age group is as more like a travel vaccine. The importance of having at 

least an individual decision-making vaccine pertains to coverage and access, and that the 

conversation should be held. There are men and women for whom this vaccine is beneficial and 

they would be put in an out-of-pocket situation to have to pay hundreds of dollars for this kind of 

protection that is safe and effective. That decision should be left between them and their doctor, 

and they should have access to coverage.

Dr. Rockwell (AAFP) requested clarity with regard to whether “individual decision-making” was 

intended to be synonymous with a “Category B” recommendation.

Dr. Cohn indicated that in February 2018 when the EtR Framework was adopted, the 3 types of 

recommendations became no recommendation, individual clinical decision-making, or routine.

In the context of the majority of the WG favoring an individual clinical decision-making 

recommendation and a minority wants to make no recommendation, Dr. Baker (IDSA) inquired 

as to whether further data would be presented during the June 2019 meeting that would 

influence this decision. She also requested information about the current uptake for HPV 

vaccine and what the slope is likely to be in the next couple of years.

Dr. Markowitz indicated that the coverage data were presented during the October 2018 

meeting;1-dose coverage was about 68% in females and 63% in males. This has been

increasing gradually every year in 13-17 year olds. That age group is aging into their 20s, so 

coverage is gradually increasing. In terms of additional data, health economic results shown 

during this session are in the process of being finalized. The WG needs to review them again 

along with the AIM survey results and feedback from ACIP.

Dr. Lee clarified that there is a difference between ACIP specifically not recommending and 

simply being silent.

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Dr. Markowitz stressed that they would not be recommending against. There would just be no 

recommendation.

Dr. Ezeanolue asked what the options would be for a vote in June.

Dr. Markowitz indicated some of the issues discussed by the WG around harmonization of the 

catch-up age. For example, for 26 versus 30, some WG members felt that vaccine providers are 

used to 26 already and it should be kept at that age. If the upper age for catch-up is changed to 

age 30 years, for example, other issues would have to be addressed such as changes to EMRs, 

IIS, and other systems. Others considered harmonization at age 30 to acknowledge the 

extended age recommendation; however, consideration of age 26 or 30 would be further 

assessed based on the health economic modeling. 

Regarding “no recommendation” which does not mean “not recommended,” Dr. Fryhofer (AMA) 

wondered if that would be similar to what ACIP did when making the transition from 4vHPV to 

9vHPV vaccination for the revaccination of adolescents and young people who received the 

4vHPV series. As she recalled, the guidance included explaining the incremental benefits for 

males and females.

Dr. Markowitz indicated that the transition from 4vHPV to 9vHPV vaccine was somewhat 

different because that decision was not brought to ACIP. That was strictly CDC guidance. In this 

case, the WG would be bringing this before ACIP.

Introduction

Kelly Moore, MD, MPH 

Chair, Combination Vaccines WG 

Vanderbilt University School of Medicine 

Dr. Moore reported that the Combination WG has been focusing on a pediatric hexavalent 

vaccine over the last couple of months. This vaccine is a joint venture with Merck and Sanofi 

Pasteur that contains the following antigens:

❑

❑

❑

❑

Diphtheria, tetanus, pertussis (DTaP5)

Polio (IPV)

Haemophilus influenzae type b (Hib; PRP-OMP)

Hepatitis B (Hep B)

This vaccine is intended to be given in a 3-dose series at 2, 4, and 6 months. The BLA was 

accepted by FDA for review in October 2015, and was approved and licensed by the FDA on 

December 21, 2018.

In terms of the policy topics under consideration by the WG, the first is to consider whether the 

new pediatric hexavalent vaccine should be included as an option in the Vaccines for Children 

(VFC) Program for the infant series at 2, 4, and 6 months of age. This is primarily a VFC 

Combination Vaccines

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question, because all of the individual components are currently licensed and recommended. 

The WG also is considering whether the new pediatric hexavalent vaccine should be 

preferentially recommended for the American Indian/Alaskan Native (AI/AN) population. A 

preferential recommendation would require an ACIP vote. The goals of the WG are to: 1) review 

published and unpublished data related to the safety and immunogenicity of the investigational 

hexavalent pediatric vaccine that is now licensed; and 2) apply the EtR framework.

The Combination Vaccine WG formed and reviewed data early and delivered a presentation 

during the October 2015 ACIP meeting in anticipation of FDA approval at that time. However, 

FDA approval was delayed due to requests for additional information by the FDA. Therefore, the 

Combination Vaccine WG took a hiatus pending FDA approval. The group re-formed in 

December 2018 upon notification of impending licensure. The WG has had three calls since 

December 2018, one in January and two in February 2019. During these calls, the WG 

reviewed the safety and immunogenicity data, reviewed Hib epidemiology and Hib vaccines 

among the AI/AN population, and discussed policy options.

Coming up, the WG will be applying the EtR framework, with a VFC vote tentatively scheduled 

during the June 2019 ACIP meeting and publication of the MMWR in Fall 2019. It is important to 

note that the manufacturer has stated that although licensure by the FDA has already occurred, 

supply will not available in the US until at least 2020.

The agenda for this meeting included presentations on the following:

❑

❑

❑

Immunogenicity and Safety of Pediatric Hexavalent Vaccine

Hib Epidemiology and Vaccines in American Indian/Alaskan Native Population

Summary, Review of Work Group Considerations

Immunogenicity and Safety of DTaP5-IPV-HepB-Hib 

(VAXELISTM): A Pediatric Hexavalent Combination Vaccine

Andrew Lee, MD 

Executive Director, Vaccines Clinical Research 

Merck & Co., Inc. 

Dr. Lee presented on the immunogenicity and safety of VAXELISTM, a pediatric hexavalent 

combination vaccine. The benefits of combination vaccines are well-known. They are comprised 

of licensed component vaccines with demonstrated safety profiles. Implementation has helped

to reduce the number of injections and has simplified the childhood vaccination schedule 1,2,3. 

They also have been shown to improve vaccination compliance and timeliness 1,2,3. 

Combination vaccines also have improved the office visit experience. There are less visits 

needed and less vaccine preparation time and time spent on administrative tasks. 6,7 This allows 

for more time to be spent on patient care6[

1Kalies H et al. Pediatr Infect Dis J 2006;25(6):507-

512; 2Marshall GS et al. Pediatr Infect Dis J 2007; 26(6):496-500; 3Happe LE et al. Am J Manag 

Care 2007; 13(9):506-512; 4Glanz JM et al. JAMA Pediatr. 2013;167(11):1060-1064; 5Omer SB 

et al. N Engl J Med 2009;360(19): 1981-1988; 6Pellissier JM et al. Am J Manag Care 

2000;6(9):1038-1044; 7Goldfarb NI et al. Managed Care 2005; 14(6 Suppl):3-12].

To address the challenges of hexavalent vaccine manufacture and development, Merck and 

Sanofi Pasteur formed a joint venture called MCM Vaccine Company in 1991. Merck contributes 

the Hib and HepB, while Sanofi contributes the DTaP5 and IPV and is responsible for final 

formulation and release of the vaccine. The development work has been split with Merck taking 

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the clinical lead and Sanofi the regulatory lead. Both companies will promote the vaccine and 

Merck holds the global safety database and leads pharmacovigilance. 

In terms of the composition of VAXELISTM, Merck makes the Hib or the polyribosyl ribitol 

phosphate (PRP) antigen. It is conjugated to the outer membrane protein complex (OMPC) 

carrier protein. This is the same as in PEDVAX HIB® vaccine, except the amount of Hib vaccine 

is less at 3 μg instead of 7.5 μg. This was the dose that resulted in optimal immunogenicity and 

safety in the Phase II study. The HepB antigen is the same as in RECOMBIVAX HB®, except in 

this case the dose has been increased from 5 μg to 10 μg to overcome potential immune 

interference with other vaccine components. Sanofi contributes the 5 antigens contained in the 

pertussis part of the vaccine. That, with diphtheria and tetanus toxoid, are equal to the 

PENTACEL® vaccine. The inactivated poliovirus (IPV) is the same as in IPOL®. The polio 

antigen numbers may look different from recent IPOL®labels, which is because of an update to 

the quantification method not to a change in the antigen amount. VAXELISTM has 0.319 mg of 

aluminium adjuvant and a fully liquid formulation that does not require reconstitution, which 

simplifies administration.

These are the indications and schedule from the VAXELISTM US Product Information (USPI).

1. INDICATIONS AND USAGE

VAXELIS is a vaccine indicated for active immunization to prevent diphtheria, tetanus, 

pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae (H. 

influenzae) type b. VAXELIS is approved for use as a 3-dose series in children 6 weeks 

through 4 years of age (prior to the 5th birthday).

2.1 VACCINATION SCHEDULE

VAXELIS is to be administered as a 3-dose series at 2, 4, and 6 months of age. The first 

dose may be given as early as 6 weeks of age. Three doses of VAXELIS constitute a 

primary immunization course against diphtheria, tetanus, H. influenzae type b invasive 

disease and poliomyelitis.

VAXELIS may be used to complete the hepatitis B immunization series.

A 3-dose series of VAXELIS does not constitute a primary immunization series against 

pertussis; an additional dose of pertussis-containing vaccine is needed to complete the 

primary series.

In terms of Hib immunogenicity data from a Phase II study of a hexavalent vaccine with different 

Hib formulations and doses, PRP-OMPC-containing formulations of the hexavalent had 

acceptable Hib responses; whereas, PRP-T formulation did not. A high percentage of subjects 

had Hib responses ≥1.0 μg/mL and high GMCs as well. The hexavalent PRP-OMPC 3 μg and 6 

μg formulations had similarly high Hib responses. The 6 μg formulation was associated with 

slightly higher rates of injection-site and systemic AEs. Therefore, the hexavalent PRP-OMPC 3 

μg dose was chosen for further development [Diaz-Mitoma et al. Vaccine 29 (2011) 1324–

1331].

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The following is a chart comparing the number of injections needed for combination vaccine 

schedules in the US, with the main point being that the VAXELISTM regimen saves 2 to 4 

injections over the PEDIARIX®regimens and 1 to 2 injections over the PENTACEL®regimen:

For the Global Phase IIb/III studies with final formulations of VAXELISTM, Dr. Lee shared 

detailed results for studies 005 and 006, which are the US studies and the basis of licensure in 

the US. In addition, he shared Hib immunogenicity results from study 008. Several European 

studies also were conducted in this program to cover the variety of immunization schedules that 

are present in the EU. Across Phase IIb, it was shown that VAXELISTM could be given with 

commonly used pediatric vaccines, and a robust safety database was provided with over 5500 

VAXELISTM recipients.

Study 005 is the pivotal non-inferiority study in the US in which VAXELISTM was compared to 

PENTACEL® and separate monovalent HepB and the immunogenicity of concomitant RotaTeq®

vaccine was evaluated. In terms of the antibody response rates, the confidence intervals were 

largely overlapping showing similar immunogenicity between VAXELISTM recipients and 

controls. The exceptions are for the Hib responses at two different thresholds, which were 

higher for VAXELISTM recipients and compared to controls. This is an expected result for these 

types of Hib vaccines. In fact, all non-inferiority criteria were satisfied for antigen response rates 

after the third dose. VAXELISTM did not meet non-inferiority criteria for the GMC measure of the 

FHA pertussis antigen. However, the vaccine response rates for filamentous hemagglutinin FHA 

were satisfied. Therefore, this non-inferiority result was not felt to be clinically significant. 

Regarding the pertussis antigen response rates after the toddler dose (e.g., the fourth dose of 

the pertussis-containing vaccine), the confidence intervals overlap and non-inferiority criteria 

were met for all pertussis endpoints. Rotavirus immunogenicity was non-inferior when given with 

VAXELISTM as compared to when it was given with control vaccine.

Study 006 looked at the immune responses to 3 consecutive lots of VAXELISTM and a control 

arm also was included. Consistent immune responses were demonstrated to all antigens across 

the 3 lots in this study. Immunogenicity of concomitant PCV13 also was evaluated. In terms of 

the responses for the 13 serotypes contained in PCV13, non-inferiority criteria were satisfied for 

12 out of the 13 types. Only serotype 6B did not meet the study non-inferiority criteria, which is 

that the lower bound of the GMC ratio should exceed 0.67. However, it is worth pointing out that 

the data would satisfy the non-inferiority criteria typically employed in the pneumococcal vaccine 

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field, which is that the GMC ratio should be > 0.5. Again, this result was not felt to be clinically 

significant. Study 006 was the largest study in the US, so it included sites with AI/AN population 

ethnicity. Before vaccination, there was low and similar baseline immunity against Hib for both 

the AI/AN subset and the study as a whole. After the third dose, there were robust immune 

responses to VAXELISTM and the non-inferiority criteria were met for the study overall. For the 

VAXELISTM arm, the post-toddler dose means 3 doses of a PRP-OMPC containing vaccine 

followed by a booster dose of PRP-T that came from the PENTACEL® booster dose. That is 

compared to the control arm, which had 4 doses of PRP-T all the way through. Both regimens 

had 100% of subjects >1.0, so robust immune responses. However, the GMC were much higher 

in the group who received the mixed regimen. This is consistent with the Hib monovalent 

literature showing that the combination of OMPC first and then PRP-T results in the highest Hib 

responses [Block et al. Ped Inf Dis J. (2017) 36:202–208].

Study 008 was conducted in Italy, Sweden, and Finland where the comparator was INFANRIX®

hexa, the licensed hexavalent vaccine in Europe. This study is representative of the 2+1 

schedule in which there are 2 infant doses and then a booster dose, in this case given between 

11 and 12 months. This study provided the opportunity to examine post-dose 2 Hib responses. 

By all measures after the second dose, the responses were higher in the VAXELISTM group as 

compared to the control. Most dramatically, the percent of subjects ≥ 1.0 was 73% in the 

VAXELISTM group compared to 27% in the control group, which clearly satisfied superiority 

criteria. Again, the combination vaccine results were consistent with the Hib monovalent 

literature that shows that there is more rapid development of immune responses with the PRPOMPC type of vaccine as compared to the PRP-T. In terms of all Hib responses in the study, 

another highlight is that before the toddler dose was given, a substantially higher proportion of 

subjects retained protective immune responses ≥ 0.15 in the VAXELISTM group as compared to 

the control. In fact, the only time that responses were higher for the control vaccine were the 

GMCs post-toddler. This is also consistent with the Hib monovalent literature [Silfverdal et al, 

Vaccine (2016) 3810–3816].

Moving on to safety, the following are the safety measurements for the Phase III studies:

❑

❑

➢

➢

❑

❑

❑

Daily temperature measurements for 5 days after each vaccination, with day of vaccination 

counted as Day 1:

38.0 ≤ Mild ≤ 38.4°C 100.4 ≤ Mild ≤ 101.1°F

38.5 ≤ Moderate ≤ 39.4°C 101.3 ≤ Moderate ≤ 102.9°F

Severe ≥ 39.5°C Severe ≥ 103.1°F

Solicited AEs for 5 days after each vaccination:

Solicited systemic AEs: fever, vomiting, abnormal crying, drowsiness, appetite loss, 

irritability

Solicited injection-site AEs: redness, swelling, and pain/tenderness

Unsolicited AEs for 15 days after each vaccination

All serious AEs from start to ~180 days (~6 months) after infant vaccination series in US and 

for 15 days after each vaccination in EU

Deaths and vaccine-related SAEs at any time during the study for all studies in the program

The incidence of solicited systemic reactions on Days 1-5 following any dose for all studies with 

safety data in the Phase III program (004, 005, 006, 007, 008, 011) in general was similar. 

There was a slightly higher rate of pyrexia or fever, otherwise the incidences were similar. The 

analyses were then narrowed to just the European studies with a hexavalent vaccine versus a 

hexavalent vaccine, and the fever rates were similar for the VAXELISTM group compared to the 

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control. Conversely, if the analyses was limited to the US studies with a hexavalent vaccine 

versus a pentavalent, there was a signal for a higher rate of fever.

Taking a closer look at fever in the US studies, combining Studies 005 and 006, there was 

approximately a 13% rate of all fever in the US studies for VAXELISTM as compared to control. 

This was driven primarily by mild and moderate fever. There was no statistically significant 

difference in severe fever rates, and the vast majority of temperature elevations in these studies 

were 2 days or less as would be expected for a component vaccine like VAXELISTM. There was 

a slight difference in fever rates after the first dose, which became wider by the second dose, 

and plateaued by the third dose. Fever-related medical events were carefully monitored in 

these studies for pyrexia, febrile convulsion, convulsion following any infant dose of vaccination

in the US studies. As a reminder, there are approximately 4 times the recipients of VAXELISTM 

as compared to control vaccine in the US studies. There was low and similar incidence of 

pyrexia SAEs for VAXELISTM as compared to controls. There were no febrile seizures within 15 

days of any infant dose of vaccination. When the period is extended to 6 months after any dose, 

there was a low and similar incidence of these events. These data support that although there is 

an increase self-limited mild to moderate fever associated with VAXELISTM, this higher rate of 

fever was not associated with medical events. The data also showed a low incidence of 

vaccine-related SAEs and study discontinuations due to AEs in both vaccine groups, with no 

statistically significant difference. The investigators determined that none of the deaths in these 

studies were vaccine-related.

To summarize the clinical data, VAXELISTM was rigorously evaluated in 6 Phase III clinical 

studies, in which a total of over 5000 infants 6 to 12 weeks of age at enrollment received at least 

1 dose of VAXELISTM. Two of these, 005 and 006, were controlled clinical studies conducted in 

the US, in which a total of 3380 infants 6 to 12 weeks of age at enrollment received at least 1 

dose of VAXELISTM. These studies show that VAXELISTM demonstrated robust immunogenicity 

and had an acceptable safety profile that is consistent with its component vaccines.

Combination vaccines improve vaccination compliance and timeliness. Hexavalent vaccines are 

not new. They have been used outside of the US for many years. VAXELISTM has been 

available in the EU since May 2017 in 4 EU countries. Over 1.5 million doses have been

distributed to hundreds of thousands of children, with no unexpected safety signals. VAXELISTM 

was recently approved by the US FDA on December 21, 2018. The Merck-Sanofi Pasteur Joint 

Venture is building up supply for a US launch. In summary, VAXELISTM will provide a new 

option for meeting the recommended US vaccination schedule with fewer injections.

Discussion Points

Dr. Stephens observed that a significant aspect of the effectiveness of Hib vaccines was herd 

immunity. Given the lower dose, he wondered if Dr. Lee could comment on herd protection with 

VAXELISTM.

Dr. Lee indicated that based on the strong immunogenicity results for Hib, they would not expect 

any difference in herd immunity due to the lower dose. They are being data-driven by the results 

seen in the formulation studies. The robust immunogenicity for Hib would predict equal herd 

immunity to what has occurred with the monovalent Hib vaccine.

Dr. Walter asked for clarification regarding whether the rates of fever increased with subsequent 

doses, and whether any of the children who were 6 months of age receive influenza vaccine in 

any of the studies.

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Dr. Lee indicated that fever rates were slightly higher for the second dose as compared to the 

first dose, but then the difference was similar between the second and third doses and then 

plateaus. In terms of the receipt of influenza vaccines, other vaccines were excluded in these 

studies that were not the study-designated vaccines within 14 days. All of the recipients for 

these studies would have received concomitant PCV13 and rotavirus vaccine.

Dr. Quach (NACI) wondered whether there was any difference in terms of formulations within 

this hexavalent vaccine and the other hexavalent vaccine used in Canada.

Dr. Lee indicated that the main difference is the Hib component. They have the PRP-T and the 

US has the PRP-OMPC. Other than that, the diphtheria, tetanus toxoid, and acellular pertussis 

(DTaP) is from a different manufacturer. This DTaP is from the Sanofi lineage. However, he 

could not comment on whether there are additional differences related to that.

Dr. Wharton (Division Director, ISD) requested further comment on the causes of death for the 6 

children who died in the vaccine group, and Dr. Romero requested additional information on the 

sepsis death.

Dr. Lee indicated that the causes of death in the VAXELISTM group were hydrocephalus, sepsis, 

2 cases of Sudden Infant Death Syndrome (SIDS), asphyxia, and unknown cause. The 

unknown cause occurred 44 days after vaccination. It was reported that the subject’s father fell 

asleep with the baby and thought that the baby had been suffocated. Details from the ED report 

revealed that the subject was found at home not breathing. The final autopsy report showed that 

the cause and manner of death were un-determinable, and the toxicology report was negative. 

The sepsis was caused by group A streptococcus, which was confirmed by autopsy. 

Haemophilus Influenzae Type B in Native American Children

Laura Hammitt, MD 

Associate Professor, Johns Hopkins School of Public Health 

Director, Infectious Disease Prevention Program, Center for American Indian Health 

Dr. Hammitt presented on Hib disease epidemiology in Native American children, the rationale 

for preferential recommendation of PRP-OMP Hib vaccine for Native American children, and 

considerations pertaining to Hexavalent use.

During the pre-vaccine era from 1965-1990, Native American children experienced a rate of 

disease that was between 2 and 10 times higher compared to the other populations around the 

world. Looking specifically at Hib meningitis in the general US population, Alaska Native 

children experienced a much higher burden of disease compared to general US children during 

the pre-vaccine era. In addition, the incidence of disease in Native children peaks at a younger 

age of 4-5 months compared to the general US at 6-9 months. Obviously, there is a substantial 

disparity in these populations. Among Native American children from the Southwest US and 

Alaskan Natives <1 year of age in the pre-vaccine era, a significant percent had Hib disease

during the first 6 months of life at 36% for American Indians and 38% percent for Alaska 

Natives. In Non-Alaskan Natives, the percent was 29%.

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Four conjugate vaccines were developed for prevention of Hib disease in infants shown below, 

two of which are available in the US, PRP-T and PRP-OMP:

❑

❑

❑

❑

PRP-D: PRP-diphtheria toxoid (ProHIBiT®)

HbOC: Hib oligosaccharide-CRM197 (HibTITER®)

PRP-T: PRP-tetanus toxoid (ActHIB®; Hiberix)

PRP-OMP: PRP N. meningitidis outer membrane protein (OMP) (PedvaxHIB®)

The correlate of protection that is generally used for Hib conjugate vaccine is based on the antiPRP antibody GMC concentration. A GMC of ≥0.15 μg/mL predicts short-term protection 

against invasive disease, while a GMC of ≥1.0 μg/mL predicts long-term protection against 

invasive disease. All four of the vaccines that were being developed for use in the US were 

studied in Alaska Native infants to assess the immunogenicity of these vaccines. PRP-OMP 

was administered as a 2-dose primary series at 2 and 4 months, which produced good 

immunogenicity. At the time of the 4-month vaccination, or 2 months following the first dose, 

91% of children had protective titers. This compares to only 11% for PRP-D, 24% for HbOC, 

and about 30% for PRP-T. Therefore, a good level of protection was achieved following one 

dose of PRP-OMP [Bulkow et al., Pediatr Infect Dis J 1993;12:484-9].

The PRP-OMP vaccine was evaluated in Phase III clinical trials on Navajo Nation in which 

children were randomized to the PRP-OMP Hib vaccine or a placebo. Again, protective antibody 

levels after the first dose were achieved in approximately 90% of children who received PRPOMP vaccine. Looking at the efficacy analysis in the intention-to-treat (ITT) cohort from the 

same trial, efficacy was 100% against disease after the first dose and before the second dose 

had been given. So, there was high immunogenetic and high efficacy following 1 dose of PRPOMP [Santosham et al., N Engl J Med 1991; 324:1767-1772].

The PRP-OMP vaccine was preferred by the Indian Health Service (IHS) given those immune 

parameters and the documentation within the Native population of demonstrated efficacy, and 

the vaccine was introduced into the general US immunization schedule in 1991. It achieved 

substantial reductions in the burden of disease. Most of this disease is Hib meningitis, which 

has a 2% to 5% case fatality rate. Of survivors, 15% to 30% have hearing loss or neurologic 

sequelae. This is a bad disease and the vaccine worked remarkably well, resulting in a 

reduction in the average annual number of cases in the pre-vaccine era of 19 cases per year 

down to about 2 cases per year in the routine use era.

In terms of what is occurring more recently, rates of disease in Navajo children continue to be 

higher than in the general US population. While a spike in disease occurred in 2016, that spike 

was not observed in 2017 or 2018. It is known that Hib continues to circulate in this population. 

With a potential new vaccine that has undocumented immunogenicity following the first dose, 

there may be some potential for disease in that situation [Grant et al, Navajo Research 

Conference 2017].

In Alaska, similar results were seen with introduction of PRP-OMP vaccine resulting in dramatic 

reductions in Hib disease in children in both Native and non-Native populations. An increase in 

cases occurred in 1996, which was associated with a change in the recommendation in the 

Alaska vaccine schedule from routine PRP-OMP to an HbOC vaccine administered as 

TETRAMUNETM to try to decrease the number of doses that were being given. Within 4 months 

of that recommendation, several cases of Hib disease occurred in rural Alaska Native infants. 

Over the course 2 years, about 16 Hib cases had occurred. Alaska responded quickly and made 

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a change in the recommendation to use PRP-OMP as the first dose followed by HbOC given as 

TETRAMUNETM for subsequent doses. However, that was still associated with an increased 

level of disease compared to the control that had been achieved with PRP-OMP vaccine. Even 

though PRP-OMP was recommended for the first dose, it was discovered that several children 

inadvertently received the HbOC vaccine which also was being stocked in the clinics for their 

first dose and were potentially left vulnerable because of that in these high transmission high 

burden settings. Since the state returned to a policy for PRP-OMP for all vaccine for all children, 

there has been sustained control of disease with occasional sporadic cases, but overall 

substantial reduction and sustained control having been achieved [Singleton, et al. J Pediatr 

2000; 137:313-20 and CDC, unpublished].

This experience in Alaska contributed to a preferential recommendation for PRP-OMP for Native 

American children, and a preference on the part of IHS providers not to stock multiple types of 

vaccines that could create an opportunity for misadministration of the non-PRP-OMP vaccine as 

the first dose. The Committee on Native American Child Health (CONACH) issued a statement 

in 1999 that, “Because of the risk of invasive Hib disease at younger ages, the Indian Health 

Service (IHS) has recommended a preference for the PRP-OMP (PEDVAX-HIB) Hib conjugate 

vaccine based on seroconversion rates of 60% after the first dose of PRP-OMP, compared with 

rates of only 20% for other Hib conjugate vaccines.” That recommendation was published 

subsequently in the Red Book in 2000 [AAP Committee on Native American Child Health, 

Pediatrics 1999].

Possible introduction of a hexavalent vaccine would change several elements related to the Hib 

vaccine experience for Native children. First, the antigen load selected for hexavalent is 3.0μg 

versus 7.5μg in PRP-OMP. The hexavalent would be given at 2, 4, and 6 months of age and the 

booster dose would be given either as a PRP-T-containing vaccine like PENTACEL® or a single 

antigen PRP-OMP booster. There is some evidence to suggest that using a mixed regimen 

could be beneficial and provide greater immunity. 

To briefly review some of the immunogenicity data, the first study evaluated Hib antigen 

concentrations at 3.0μg PRP-OMP vs. 6.0μg PRP-OMP vs. 12.0μg PRP-T compared to a 

control. Immunogenicity was evaluated at post-dose 3 at 7 months. As mentioned earlier, the 

immunogenicity was very good for both PRP-OMP at 3.0μg and PRP-OMP at 6.0μg. Because 

of the more favorable reactogenicity profile, the product moved forward with a 3.0μg PRP-OMP 

component1. The trial in Europe that evaluated a 2+1 schedule and assessed post-dose 2 

immunogenicity of the hexavalent vaccine again showed that there was very good response 

post-dose 2 in terms of percent of responders and a 2.4 GMT2

 [1Diaz-Mitoma, et al., Vaccine

2011; 29:1324-1331; 2 Silfverdal et al., Vaccine 2016; 3810-3816].

Plotting the GMT of 2.4 in the context of a variety of historical data on post-dose 2 

immunogenicity of PRP-OMP in Native American children, general US children, and the 

hexavalent from the European study, the data are very reassuring that the post-dose 2 

immunogenicity is comparable to what has been observed and provides good protection. The 

post-dose 3 data also reflect a very good GMC.

When the available data are synthesized together in terms of what it means for use of 

hexavalent vaccine in Native populations, it is known that there are good protective GMCs for 

hexavalent vaccines post-dose 2 and post-dose 3. Overlaying the epidemiology of Hib disease 

in Native American infants, a substantial amount of disease is known to occur early in life. Given 

that there are no immunogenicity data for hexavalent post-dose 1, there is a question regarding 

whether there may be a window of vulnerability in a setting of continued circulation of disease. It 

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may be that hexavalent provides great immunity after 1 dose, but given that the vaccine antigen 

load is lower, there just are no data to substantiate this.

In conclusion, Hib is still circulating in Native American rural and reservation-based 

communities. Post-dose 2 immunogenicity looks great, but post-dose 1 immunogenicity is 

unknown for the hexavalent vaccine and that may create a window of vulnerability in children 

between doses 1 and 2. This can be exacerbated depending upon timeliness of vaccine. 

Establishing immunogenicity post-dose 1 in high-burden Native American populations is 

important and could inform policy.

Summary & Review of Work Group Considerations

Sara Oliver MD, MSPH

CDC WG Lead, Haemophilus Influenzae Subject Matter Expert 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Oliver presented a brief summary of the information the WG reviewed, as well as the WG 

considerations. As a reminder, two policy topics under consideration were discussed by the 

WG, which were to: 1) consider if the new pediatric hexavalent vaccine should be included as 

an option in the VFC Program for the infant series at 2, 4, and 6 months of age; and 2) consider 

if the new pediatric hexavalent vaccine should be preferentially recommended for the American 

Indian and Alaskan Native population.

Information on a variety of topics was reviewed by the WG. The WG members and CDC SMEs 

for each relevant pathogen reviewed immunogenicity data for the pediatric hexavalent vaccine.

In addition, the WG reviewed data on the safety of the hexavalent vaccine. Next, given that the 

Hib component in the hexavalent vaccine is PRP-OMP, they reviewed Hib epidemiology and the 

history of Hib vaccines in the AI/AN population. Finally, they reviewed available data on the 

pediatric hexavalent vaccine and the AI/AN population specifically. Dr. Oliver briefly summarized 

their discussion on each topic.

In terms of the immunogenicity data for the infant series, given that all components of the 

pediatric hexavalent vaccine are currently licensed and recommended, the immunogenicity 

studies conducted were non-inferiority studies comparing the new pediatric hexavalent vaccine 

to currently licensed vaccines. Overall, non-inferiority criteria were met, with 2 exceptions. First, 

non-inferiority was not met for the geometric mean concentrations for one pertussis antigen, 

FHA, at the post-dose 3 time point. However, it was achieved with the percent that met a prespecified vaccine response. Next, one pneumococcal antigen, 6B, missed the pre-specified 

non-inferiority endpoint of 0.67 post-dose 3. However, it would have met the non-inferiority 

endpoints used in the PCV13 studies.

These data were reviewed with the WG. Overall, because antigen or serotype-specific 

correlates of protection are unknown, it is unclear whether these differences are clinically 

relevant. However, there are 5 pertussis antigens included in the vaccine, and only one antigen 

at one time point did not meet the pre-set non-inferiority criteria. In addition, the non-inferiority 

criteria were met for all other PCV13 antigens. Serotype 6B rarely causes invasive 

pneumococcal disease (IPD) among US children in the post PCV13 era. Therefore, the WG did 

not have serious concerns regarding the immunogenicity data, but did feel that post-licensure 

monitoring will be important moving forward.

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Next, the WG reviewed the safety data. The pediatric hexavalent vaccine has a safety profile 

consistent with the licensed component vaccines. Overall, there was a higher rate of fever, 

particularly when compared to pentavalent regimens. However, there was no increase in feverrelated medical events, such as hospital visits or febrile seizures. The WG also had no serious 

safety concerns, but again felt that post-licensure monitoring would be important moving forward 

for safety as well.

After reviewing these data, the WG discussed including this vaccine as an option for the infant 

series. Overall, the WG is supportive of including this vaccine in the VFC program as a 

recommended option. The WG was in agreement on this. 

Next, the WG discussed data that could inform a possible preferential recommendation for the 

pediatric hexavalent vaccine in the AI/AN population. In the pre-vaccine era, Hib disease 

occurred at a younger age among the AI/AN population compared to the general US population.

In addition, PRP-OMP vaccines can achieve protective immunity in a majority of infants after the 

1

st dose. It is because of these factors, to provide protection early in infancy, that PRP-OMP 

vaccines have a preferential recommendation for the AI/AN population.

The new pediatric hexavalent vaccine, VAXELISTM, is the same antigen and manufacturer as 

the currently available PRP-OMP vaccine, PedvaxHIB®. However, there are different amounts of 

antigen in the 2 vaccines, as shown here:

❑

❑

PedvaxHIB®: 7.5μg PRP-OMP

VAXELISTM: 3μg PRP-OMP

In addition, as was just presented, the preferential recommendation for PRP-OMP vaccines was 

based on immunogenicity data after the first dose. The available data for VAXELISTM shows a 

robust response. Data are available post-dose 2, post-dose 3, and post-toddler dose. However, 

there are no data post-dose 1. Therefore, considering these data, the current thoughts 

regarding a possible preferential recommendation are that the WG feels that immunogenicity 

data post-dose 1 is needed before ACIP considers a preferential recommendation. The WG 

also was in agreement on this. 

Next, the WG will apply the EtR Framework to present during the June 2019 meeting in 

anticipation of a potential VFC vote. 

Discussion Points

Dr. Bernstein inquired about the impact on nasopharyngeal carriage from PRP-OMP and how it 

compared to the other Hib vaccine, and specifically why there is continued Hib disease in the 

AI/AN population.

Dr. Oliver said that she did not know about nasopharyngeal carriage differential, but overall the 

Hib vaccines reduce carriage. The disease currently circulating is in a slightly older age group. 

Vaccinated children who are receiving disease are slightly older.

Dr. Hammitt added that there are good data from Alaska that PRP-OMP vaccine does reduce 

carriage, but the very high burden, high transmission setting drives this. The same is observed 

with pneumococcal colonization. Vaccine works well to reduce that, but does not fully reduce it 

to levels seen in the rest of the US.

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Dr. Walter asked whether a study is planned in the AI/AN population to acquire post-dose 1 

immunogenicity data.

Dr. Lee indicated that this is of interest and Merck is assessing options on how to collect those 

data.

Dr. Frey expressed concern that the AI/AN incidence of pneumococcal disease occurred at 4 

months in the post-dose 2 data, but after the hexavalent data this is not seen until 6 months and 

that is at 73%. While post-dose 3 looks great, 73% is somewhat low and she wondered how that 

compares to the pentavalent vaccine.

Referring to his Slide 18, Dr. Lee clarified that 73% referred to threshold of ≥ 1.0, which is the 

level associated with long-term protection. The percent ≥ 0.15 is the level needed for protection, 

which is quite high at 97%. Those results are quite reassuring.

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier provided CDC updates on measles, a Notice of Funding Opportunity (NOFO) for 

the 2019-2023 Immunization and Vaccines for Children (VFC) Cooperative Agreement, and an 

article recently published in the Journal of Pediatrics.

From January 1, 2019 to February 21, 2019, there have been 159 confirmed cases of measles 

reported from 10 states. Among these, there are 6 ongoing outbreaks: Clark County, 

Washington; New York State (Rockland County, Monroe County, and New York City); Harris 

County, Texas; and Champaign, Illinois. These outbreaks are generally linked to either 

unvaccinated US travelers who travel overseas, are exposed to measles, and bring them back 

to the US or travelers from outside the US visiting the US and exposing families and 

communities. The large outbreaks are definitely in close knit populations of smaller ethnic or 

religious persuasion who are clustering together and are by and large unvaccinated. The burden 

to respond is primarily on local and state health departments. In each of these outbreaks, there 

are thousands of contacts to trace in order to address outbreaks quickly. CDC is providing 

technical expertise, already has staff embedded in these states, has staff with boots on the 

ground, and has the communication team working the states to support their efforts. For 

comparison, in 2017 there were 17 outbreaks. Of those, 3 were in New York State, New York 

City, and New Jersey. These outbreaks were associated primarily with Israel where an 

extremely large outbreak is occurring. On February 26th, Dr. Messonnier testified before the 

House Committee on Energy and Commerce, along with Dr. Fauci from the National Institutes 

of Health (NIH), on the threat of measles and the threat to people who are unvaccinated.

Everyone on the Committee was very supportive of the efforts to let people know that the threat 

is ongoing and there are safe and effective vaccines.

Second, the NOFO for the 2019-2023 Immunization and VFC Cooperative Agreement was 

released on February 25th. This is CDC’s primary funding opportunity for eligible state, local, 

and territorial immunization programs and supports a wide range of programs, including VFC; 

adult and adolescent immunization initiatives; vaccine access, communication, and education; 

coverage assessments; registries; and pandemic preparedness. To begin planning, 

representatives from 64 currently funded programs visited CDC in January for a kick-off 

Agency Updates

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meeting. The 64 currently funded immunization programs represent all 50 states, the District of 

Columbia (DC), 5 cities, 5 territories, and 3 federally associated state entities.

The previous week, the Journal of Pediatrics published an article on the association of provider 

recommendations in HPV initiative among male adolescents aged 13-17. This is the first 

assessment of state-specific HPV vaccination among male adolescents by provider 

recommendations. Regarding a few of the findings, HPV vaccination coverage among males 

increased significantly. The prevalence of provider recommendations also increased from 14% 

in 2011 to 65.5% in 2016, which is a great sign of success. However, there is a difference in 

provider recommendations by state. It is definitely possible to do better, especially in states 

where parents report that provider recommendations are not so strong. It is known that the 

primary driver of vaccination in any age group, especially for HPV, is the strength of provider 

recommendations. CDC will be considering ways to target education and communication 

activities to focus on the states where there is still room to grow.

Department of Defense (DoD)

Dr. Deussing expressed DoD’s appreciation for ACIP’s and CDC’s continued inclusion of the 

DoD in the ACIP meeting and ACIP WGs. He provided 3 updates for the DoD for ACIP’s 

awareness. First regarding yellow fever (YF) vaccines, like so many others, DoD is happy to 

learn of the new YF vaccine facility that has been approved by the Center for Biologics 

Evaluation and Research (CBER) and awaits arrival of vaccine supply. It is anticipated that DoD 

will continue on its current restrictions of YF vaccine utilization until the nationwide vaccine 

supply exceeds demand. The second update is with respect to influenza vaccine effectiveness. 

DoD researchers have initiated a study called A Pragmatic Assessment of Influenza Vaccine 

Effectiveness in the DoD (PAIVED). This Institutional Review Board (IRB)-approved study 

assesses influenza vaccine effectiveness among egg-derived, cell culture-derived, and 

recombinant protein vaccines. Per protocol, the available licensed vaccines were randomly 

allocated to consenting volunteers who presented to receive influenza vaccine. These 

individuals are being followed to assess whether influenza attack rates differ based upon 

vaccine received. This study began in the fall of the 2018-2019 season across several DoD 

sites in the US. Finally, a note with respect to vaccine redistribution. Vaccine redistribution in the 

DoD continues to be a widely successful program. Individual DoD immunization sites have the 

capability to communicate near expiring vaccines surplus or a vaccine deficit through personnel 

at the Immunization Healthcare Branch (IHB) at the Defense Health Agency (DHA). IHB staff 

then can reach out to other immunization sites to redistribute vaccine as needed. In FY 2018, 

$740,000 worth of vaccines were successfully redistributed using this mechanism.

Department of Veterans Affairs (DVA)

Lori Hoffman-Högg reported that over 1.8 million veterans received free influenza shots during 

FY 2018. The VA continues to partner with Walgreen’s during the current 2018-2019 influenza 

season. This partnership resulted in over 105,000 vaccines paid for by the VA during the 2017-

2018 influenza season. VA also released an updated National Electronic Decision Support Tool, 

also called National Clinical Reminder, for HepB immunization. This clinical reminder can be 

used in the Veterans Health Information Systems and Technology Architecture (VistA), the VA’s 

electronic medical record (EMR). The VA continues to align electronic measures with the 

Healthcare Effectiveness Data and Information Set (HEDIS). When VA is compared to HEDIS,

HEDIS technically captures influenza vaccine information via survey methodology. VA collects 

influenza information using both survey and chart abstraction. VA exceeds HEDIS measures for 

influenza vaccines for both adults aged 18 to 64 and 65 and older. 

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Food and Drug Administration (FDA)

Dr. Fink reported notable approvals since the October 2018 ACIP meeting. VAXELISTM, the 

hexavalent pediatric vaccine indicated for use in children 6 weeks to 4 years of age, was 

approved in December 2018. A 0.5 mL dose of Fluzone® seasonal inactivated influenza vaccine 

(IIV) was approved for use in children 6 months to 35 months of age in January 2019. Also in 

January 2019, a second dose of Adacel®(Tetanus Toxoid, Reduced Diphtheria Toxoid and 

Acellular Pertussis (Tdap) Vaccine Adsorbed) was approved for use in individuals who received 

a first dose of either Adacel® or another Tdap vaccine at least 8 years prior, or at least 5 years 

prior in the case of wound management. In other FDA news, the Vaccine and Related Blood 

Products Advisory Committee (VRBPAC) will be convened on March 6-7, 2019 at the White 

Oak Campus in Silver Spring, Maryland. During the first day of this meeting, VRBPAC will be 

discussing strain selection for the 2019-2020 seasonal influenza vaccines. They are still waiting 

for the WHO recommendation for the H3N2 strain component of those vaccines, so they will not 

be able to make a recommendation during that meeting. VRBPAC is committed to ensuring 

minimal downstream effects on influenza vaccine availability for the 2019-2020 season, and 

they hope to have additional information about next steps during the March meeting. On the 

second day of the meeting, VRBPAC will be discussing the safety and effectiveness of 

Dengvaxia®, which is a live attenuated dengue vaccine intended for use in individuals 9 through 

45 years of age with laboratory-confirmed prior dengue infection who live in endemic areas.

Health Resources and Services Administration (HRSA)

Dr. Nair provided an update on the National Vaccine Injury Compensation Program (VICP). 

HRSA continues to process an increased number of claims. In Fiscal Year (FY) 2018, there 

were 1243 claims. In that same FY, petitioners were awarded $226 million and attorneys were 

awarded $26.9 million. That includes fees to attorneys for cases that are compensated or 

dismissed, as well as interim fees. For this FY, 411 claims have been filed as of February 1, 

2019. Petitioners and attorneys have been awarded $74.4 million. Because of the increased 

number of claims in recent years, there is a backlog of 726 claims that are awaiting review by 

Medical Officers. More data about the VICP can be obtained on the HRSA website. To provide 

a broad picture for this program, from 2006-2017, HRSA received 6000 petitions that were 

adjudicated. Of those, 4000 (roughly 70%) were compensated. During that same time period 

according to CDC data, about 3.4 billion doses of vaccine were distributed in the US. For 

approximately every 1 million doses of vaccine distributed, the VICP compensates 1 claim. 

Indian Health Service (IHS)

Dr. Weiser reported that IHS has held regular calls with area and local Immunization 

Coordinators and clinicians to promote influenza vaccine uptake for 2019. Through its influenza 

surveillance system, IHS estimates that they have administered at least 295,000 doses of 

influenza vaccine with a population coverage estimate of about 35% among those 6 months of 

age and older. Uptake was highest among vulnerable populations, young children, and elders. 

Approximately 58% of children 6 months to 23 months of age received at least 1 dose of 

influenza vaccine. About 49% of elders 65 years of age and older received an influenza vaccine 

this season. IHS has a mandatory influenza vaccination policy for healthcare personnel (HCP). 

This policy requires HCP to receive the influenza vaccine each year. Healthcare employees are 

defined as anyone working within a healthcare facility. As of December 31, 2019, approximately 

93% of all HCP working for IHS had received their influenza vaccination. The policy applies only 

to employees operated directly by IHS, not the Tribally-Operated 638 Programs or the Urban 

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Indian Health Program (UIHP). However, those programs are encouraged to adopt this policy 

and many led the way for IHS by adopting the policy before IHS did. The IHS has not been 

directly impacted by the current outbreaks of measles in the Pacific Northwest or in other parts 

of the country, but has worked to get the word out about the benefits of measles vaccination and 

resources on the IHS website. IHS’s first-dose measles, mumps, and rubella (MMR) coverage 

among children 19 months to 35 months is currently 86.5% as of December 2018. Among 

adolescents 13 through 17 years of age, 95.8% have received both doses of MMR vaccine. IHS 

continues to focus its efforts toward vaccination at all ages both with influenza and the routine 

schedule of vaccines. Dr. Weiser expressed IHS’s appreciation for the discussion that was held 

the previous day regarding the Hib vaccine for Native American/Alaskan Native populations.

National Institutes of Health (NIH)

Dr. Beigel highlighted a few clinical trials and funding opportunities that might be of interest to 

ACIP. The NIH continues to have a focus on and intense interest in influenza, specifically H7N9. 

One H7N9 study was completed in November 2019 and two additional studies began since the 

last ACIP meeting, with and without adjuvant, in an effort to stay ahead of the need for an H7N9 

vaccine. NIH also has begun a Phase I study for a tuberculosis (TB) vaccine, which is critical for 

controlling TB. This is a thermostable vaccine that holds a lot of promise, so NIH is very excited 

about this. There is an opportunity for Advancing Research Acute Flaccid Myelitis (AFM). New 

applications are being accepted to support basic, translational, and clinical research in that field.

There also is an active program announcement for Research to Advance Vaccine Safety, which 

has been underway since 2009 and for which there are multiple awards. The links to all of these 

trials and announcements will be provided in the minutes. 

National Vaccine Program Office (NVPO) / National Vaccine Advisory Committee (NVAC)

Dr. Beckham, Acting Director of the NVPO and Director of the Office of HIV/AIDS and Infectious 

Disease Policy (OHAIDP), reported that NVAC released a report titled, “Strengthening the 

Effectiveness of National, State, and Local Efforts to Improve HPV Vaccination Coverage in the 

United States: Recommendations From the National Vaccine Advisory Committee in February 

2018.” Since the release of this report, NVPO has been working to address several of the 

recommendations from this report. NVPO, in coordination with offices within the Office of the 

Assistant Secretary for Health (OASH) and other agencies at the Department of Health and 

Human Services (HHS) such as CDC, have established a 3-pronged strategy for increasing 

HPV vaccination rates. The strategy focuses on engagement and communications, Integrated 

Delivery Network (IDN) health systems, and determining rural and faith-based needs. As part of 

its engagement in communication efforts, HHS will kick off communication activities on March 

4

th, which is International HPV Awareness Day.” These activities are designed to engage a 

broad range of partners to raise awareness and share evidence-based practices for increasing 

HPV vaccination rates. The kick-off will include the release of an HHS statement on HPV; an 

HHS.gov blog from ADM Brett P. Giroir, MD, the Assistant Secretary for Health (ASH); and a 

Twitter chat with the Surgeon General and other partners. Everyone can join them in raising 

awareness by using #EndHPVCancers on social media or by joining the HHS Twitter chat and 

sharing resources from the HHS HPV Toolkit. Promotional efforts will continue through April 

2019. They also will be working with CDC to engage IDN systems and a learning collaborative 

for sharing best practices. Regarding adult immunization, in addition to HPV activities, NVPO 

has been collaborating with a number of partners to improve adult immunization rates. Guided 

by the Adult Immunization Plan, NVPO is working closely with HHS regional offices to 

coordinate stakeholder meetings across the country. These meetings will focus on pressing 

regional immunization topics such as access, HepA, and HPV vaccination. Meetings are 

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planned in Regions 1, 2, 4, and 10. For adult immunization, NVPO also is co-sponsoring the 

National Adult and Influenza Immunization Summit with CDC and the Immunization Action 

Coalition (IAC). The summit will be held at CDC May 14-16, 2019. The current National Vaccine 

Plan will expire in 2020. Over the next year, NVPO will be working with CDC, NIH, FDA, and 

other stakeholders to update this plan. The expectations are that this will involve a shorter 

timeframe of 3 to 5 years versus the previous plan, which was 10 years. This will allow for more 

flexibility and the ability to address emerging challenges and/or new technologies. In addition, 

the plan will include metrics for success and implementation strategies for meeting the goals. 

During the next year, NVPO will be holding listening sessions to gain feedback from 

stakeholders that will be used to inform the development of the plan. The next public NVAC 

meeting will be convened via webcast on March 25, 2019. This meeting will focus on access, 

and an agenda will be available in the coming weeks.

Introduction

Grace Lee, MD, MPH

Pneumococcal Vaccines WG Chair

Advisory Committee on Immunization Practices

Dr. Lee reminded everyone that the Pneumococcal Vaccines WG’s terms of reference are to: 1) 

Review current data on efficacy, effectiveness, immunogenicity, and cost-effectiveness of 

pneumococcal vaccines; 2) Review current recommendations considering up-to-date (UTD) 

evidence, including epidemiological studies conducted post-licensure, and assess strength of 

the evidence; and 3) Revise or update recommendations for pneumococcal vaccine use, as 

needed.

ACIP recommended pneumococcal conjugate vaccine (PCV)7 for children in 2000, followed by 

PCV13 in 2010 when that became available. In 2012-2013, ACIP recommended PCV13 for 

individuals with immunocompromising conditions. In 2014, ACIP recommended PCV13 in series 

with PPSV23 for adults ≥65 years of age. Presently, the WG is re-evaluating the use of PCV13 

in adults ≥65 years of age. When ACIP recommended PCV13 in series with PPSV23 for adults 

≥65 years of age in 2014, the rationale was that the recommendation was in the short-term

because there was still a significant burden of disease among older adults, particularly due to 

pneumococcal pneumonia. The long-term public health benefits at that time were expected to 

be limited since the indirect effects from the pediatric PCV13 use were expected to increase. 

Therefore, the recommendation was made in 2014 with a commitment to re-evaluate this policy 

4 years later and revise it as needed.

The policy question the WG is examining is, “Should PCV13 be administered routinely to all 

immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV 

use experienced to date?” The population of interest is immunocompetent adults ≥65 with and 

without chronic medical conditions, but not the immunocompromised population. The 

intervention is PCV13 in series with PPSV23 in the context of indirect effects. The comparison is 

PPSV23 alone, again in the context of indirect effects. The core outcomes are invasive 

pneumococcal disease (IPD), pneumonia, mortality, and safety.

Pneumococcal Vaccines

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The following table is intended to emphasize that the WG is focused on the red box in the right 

upper half of the following table and looking at the PCV13 recommendation for those ≥65 years

in immunocompetent patients with and without chronic health conditions. The WG is not reconsidering the recommendation for immunocompromised persons, persons with functional or 

anatomic asplenia, Cochlear implants, or cerebrospinal fluid (CSF) leaks:

Dr. Lee indicated that during this session, presentations would focus on the following topics:

❑

❑

❑

❑

PCV13 Direct and Indirect Effects on Serotype 3 Disease 

PCV13 Direct Effects on Pneumonia Hospitalizations in Adults 

A comparison of Economic Analyses of PCV13 Use Among Adults ≥65 Years Old 

GRADE and EtR for PCV13 Use Among Adults ≥65 Years Old in the Setting of Sustained 

Indirect Effects 

Given that the goal is transparency in the decision-making process, Dr. Lee indicated that the 

WG would like ACIP members to consider the following:

❑

❑

What is the balance of desirable and undesirable effects of PCV13 use in immunocompetent 

adults ≥65 years, in the context of indirect effects from the pediatric program?

Considering values, acceptability, resource use, and implementation issues, what is your 

overall assessment of continued PCV13 use in immunocompetent adults ≥65 years?

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❑

➢

➢

➢

❑

The WG also wanted to acknowledge head-on some of the unique challenges posed by this 

particular decision:

Although the focus was on the adult decision during this session, the WG wanted to 

emphasize that the pediatric vaccination programs are far more effective at reducing 

the overall burden of pneumococcal disease due to vaccine-type strains. Some of 

the members in the WG have found it challenging to consider these 

recommendations incrementally rather than holistically. Nonetheless, they would like 

ACIP to focus just on the particular question of interest during this session. 

The second challenge for this WG has been the issue of framing bias. Even though 

the health and economic impacts of the intervention remain the same, whether 

implementing or de-implementing a recommendation, some of the WG members feel 

that it is harder to make the decision when it is framed as a loss instead of a gain.

The WG also is aware of potential new vaccines that will require .ACIP to re-evaluate 

this recommendation in the future

What additional information is needed to help determine whether continued PCV13 use in 

adults ≥65 years is warranted?

In terms of the near future pneumococcal conjugate Vaccines, there are two new products in 

Phase 3 trials: PCV15 and PCV20. Both are conjugated to CRM197 and both are working 

towards licensure in adults first. PCV15 includes PCV13 serotypes plus 22F and 33F, and is 

currently in adult Phase 3 trials. Based on information currently posted on clinicaltrials.gov, the 

manufacturer is projecting adult Phase 3 trial completion by approximately the third quarter of 

2020. PCV20 includes PCV13 plus 8, 10A, 11A, 12F, 15B, 22F, and 33F. PCV20 also is 

currently in adult Phase 3 trials. The manufacturer is projecting adult Phase 3 completion by the 

end of 2019 or early 2020 according to what is posed on clinicaltrials.gov.

PCV13 Effects on Disease Caused by Serotype 3

Tamara Pilishvili, PhD MPH 

Respiratory Diseases Branch 

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Pilishvili began by explaining the rationale for the focus on Serotype 3 (ST3) out of the 13 

types that PCV13 vaccine covers. ST3 causes most of the remaining PCV13-type disease 

burden in the US and countries using PCV13. Evidence on PCV13 effectiveness against ST3 

disease is not consistent across settings and studies. Assumptions around PCV13 effects on 

ST3 disease influence estimates of expected vaccine impact and results of economic analyses.

In terms of background, ST3 pneumococcal strains have unique genetic, phenotypic, 

physiologic characteristics associated with invasiveness and disease severity. Temporal 

variations in the incidence of ST3 have been reported that are potentially unrelated to vaccine 

introduction. To date in the literature, there are various mechanisms by which reduced 

effectiveness against ST3 is explained. Animal model studies have demonstrated that the very 

thick mucoid ST3 capsule releases free polysaccharides,1 which interferes with antibodymediated bacterial killing and protection. It also has been shown that there is reduced 

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opsonophagocytosis due to increased thickness and density of the polysaccharide capsule2

[

1Choi et al. Clin Vaccine Immunol. 2016; 2Poolman et al. Vaccine 2009].

A study conducted in the UK by Andrews et al had a primary objective to evaluate the 

effectiveness of PCV13 against individual serotypes using indirect cohort analyses. This study 

measured the effectiveness against ST3 to be 26%, with very wide confidence intervals of -69 to 

68. As part of this study, the investigators also re-evaluated the serologic threshold for 

protection on a serotype-specific basis as opposed to the accepted 0.35 threshold, which is an 

aggregate for all serotypes. They estimated that for ST3, the threshold of protection was 2.83 

and was much higher than for other PCV13 serotypes, which ranged from 0.16 to 1.00.1 It is 

known that the threshold for protection against acquisition of nasopharyngeal (NP) carriage is 

much higher than those for IPD, which is what they estimated in this study and is what the 0.35 

aggregate refers to. Studies to date have shown that there is no impact of PCV13 on acquisition 

of ST3 carriage.2 Most of the studies showed lack of impact on carriage. Therefore, no herd 

effects are expected from the childhood PCV13 programs [1Andrews et al. Lancet ID 2014; and 

2Summary of systematic review for WHO SAGE Position paper. February 2019 

(https://www.who.int/immunization/documents/positionpapers/en/)].

Dr. Pilishvili summarized what is known about PCV13 effects on IPD caused by ST3, presenting 

studies on effectiveness in children, population-level impact in children and adults (indirect 

effects), and effectiveness in adults.

Out of 6 studies on the effectiveness of PCV13 against ST3 IPD in children, only 2 were able to 

demonstrate significant effectiveness against ST3. A US study by Moore (2015) showed 80% 

effectiveness with ≥1 dose among children 2-59 months of age. This was conducted during the 

time that there was a transition from PCV7 to PCV13, so most of the children in this study 

received 2 or more doses of PCV13. Therefore, it is somewhat of an “apples and oranges” 

comparison” when looking across studies of how children were receiving PCV13 in these 

effectiveness studies.

A multi-center network study on pneumococcal disease surveillance that comes from the EU

examined effectiveness by serotype and evaluated effectiveness by time since the last dose of 

vaccine was received. Even though for PCV7, PCV13, and 19A as a group they showed that 

effectiveness was similar at ≤12 months since the last dose and ≥12 months after the last dose, 

for ST3 they showed that there may be some evidence of waning of protection. At ≤12 months 

since the last dose, ST3 effectiveness was measured at 73% and was significant; whereas, at 

≥12 months after the last dose, it was 30% and the estimate did not reach statistical significance 

[Hanquet G. and Savulescu C, unpublished data].

On February 22, 2019, WHO released a revised statement on pneumococcal vaccine use in 

children. This statement was informed by a very large body of evidence through systematic 

review of primary evidence on immunogenicity and effectiveness against IPD, pneumonia, and 

NP carriage for PCV10 and PCV13 in children for 2 products that are currently available in the 

world, PCV10 and PCV13. An excerpt directly from the statement that relates to PCV13 effects 

on ST3 IPD states that, “Despite immunogenicity data, evidence for a direct or indirect reduction 

in IPD due to serotype 3 after administration of PCV13 was inconclusive, although most studies 

showed no effect.” This evidence included effectiveness and impact studies. Of note, PCV10 

does not contain serotypes 3, 19A, and 6A. There is a statement related to product choice in the 

same position statemen that, “Both PCV10 and PCV13 have substantial impacts against 

pneumonia, vaccine-type IPD, and NP carriage . . . PCV13 may have an additional benefit in 

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settings where disease attributable to serotype 19A or serotype 6C is significant.” Yet, there is 

no mention of ST3 because of the statement above.

Data from the Active Bacterial Core Surveillance (ABCs) system have been updated through 

2017. These data reflect dramatic reductions in the incidence of vaccine serotypes among 

children less than 5 years of age. Most of the reductions were driven by serotype 19A, but 

significant reductions were observed in serotype 7F and the cross-reactive serotype 6C. While 

some overall annual changes have been seen in ST3, there has been no net impact on ST3 

disease. Looking strictly at before versus after vaccine introduction, there was a non-significant 

31% reduction (-67, 44). To understand whether there were any long-term changes in ST3 in 

children, a longer timeframe was examined from 1998-2017. Instead of trying to attribute any 

changes to vaccine introduction, a joint point analysis was conducted to allow the data to show 

whether the changes in ST3 disease trends occurred. This analysis found that ST3 rates seem 

to have been increasing before PCV7 introduction, and some time in 2003 (2000, 2008) began 

to decrease. The confidence interval is wide and does not include the PCV13 introduction 

timeline, in which reductions have been seen in type 3 disease. That trend started way before 

PCV13 was introduced in the US [Active Bacterial Core Surveillance, CDC unpublished data].

In another study from the same European network mentioned earlier, this time looking at the 

impact at a population level from various countries using PCV13 and others using PCV10. 

Countries exclusively using PCV13 initially saw what appeared to be a reduction in ST3 

disease. However, they have seen increases since 2014 in ST3 in PCV13 countries. In 

countries using PCV10, 2 of which have a combination of PCV10 and PCV13, no changes have 

been observed in ST3 during the entire time period. The indirect effects among adults >65 years

from the same network analysis showed very similar results as direct effects on disease among 

children. The rate ratios were below 1.0 through 2014 in PCV13 countries, suggesting that there 

might be a reduction in type 3 disease. However, increases since 2014 have returned to the 

same levels such that the net change was a 12% increase. There appears to have been more of 

a steady increase in ST3 in PCV10 countries, although the confidence intervals are very wide 

because fewer sites were included in this analysis [Hanquet G. and Savulescu C, unpublished 

data].

Returning to the ABCs system, between 2010 and 2014 reductions have been observed in all 

PCV13 serotypes with the exception of ST3 through indirect effects. Annual changes have been 

observed since adult vaccine introduction in 2014, though this has been less than 1 

case/100,000. Overall, there has been no change in ST3 disease even after the 2014 

recommendations. A similar joint point analysis was conducted in adults to determine where the 

change in ST3 occurred, with a very similar finding in which there seems to be a natural cycle of 

disease incidence which may have started decreasing sometime around 2000 (2000, 2003) 

before PCV7 was introduced. That trend continues and the epidemiology shows in recent years 

that in 2016-2017, ST3 caused most of the invasive disease infections in adults ≥65 years of 

age and none of the vaccine serotypes rank as the top 10 anymore. An effort also was made 

with the ABCs data to try to understand the contribution of the direct versus indirect effects to 

the observed trends. To that end, a mathematical model was constructed that uses the 

coverage data and the surveillance data before and after the vaccine was introduced. The 

bottom line results from that model in terms of the US, 190 (-470-870) cases were averted due 

to direct effects of PCV13 use in adults between August 2014 and May 2017. The very wide 

confidence intervals suggest that there may be no change. When ST3 was excluded in the 

same model, an estimated 580 (120, 1080) cases were prevented with a significant confidence 

interval. Again, showing that ST3 seems to be diluting the ability to evaluate the direct impact 

on adult disease [Active Bacterial Core Surveillance, CDC unpublished data].

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A case-control study evaluating PCV13 effectiveness among US Medicare beneficiaries ≥65 

years of age by vaccine serotype group examined PCV13 types as a group and excluding ST3, 

with sufficient power also to assess ST3 alone. Looking at PCV13 types without ST3, the 

estimate was 67% (11, 88) and was significant. The estimate was lower for ST3 alone at 26% (-

58, 65) and did not reach statistical significance CDC’s [Active Bacterial Core Surveillance and 

CMS collaboration, unpublished data].

A post-hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults

(CAPiTA), an RCT in the Netherlands of Dutch adults ≥65 years old (n=84,496), showed 100% 

efficacy. However, the objective of this trial was to evaluate the effectiveness against vaccinetype community-acquired pneumonia (CAP), so IPD and serotype-specific effectiveness were 

not the primary targets of this trial. This study was underpowered to look at ST3 IPD, with 0 

cases in the PCV13 arm and 4 cases in the control arm. This translated into 100% efficacy (-52, 

100), but the confidence interval is obviously not significant because the study was not powered 

to examine that [Bonten MJM, et al. NEJM. 2015; Gessner et al. In press].

Moving on to PCV13 effects on pneumonia caused by ST3, limited studies are available 

evaluating serotype-specific pneumonia burden and VE because there are no commercially 

available tests to detect pneumococcal serotypes causing non-bacteremic pneumonia. Dr. 

Pilishvili presented data from studies utilizing the Pfizer-developed serotype-specific urine 

antigen test (SSUAD), which are the only studies that can look at the specific outcome of 

PCV13 effectiveness against ST3 pneumonia. In the original CAPiTA trial population for the per 

protocol analysis for ST3 pneumonia, effectiveness was 56% (-12, 86) but the 95% confidence 

interval did not reach across the null value. For the ITT analysis in which individuals who were 

included who later developed immune compromise or other protocol violations that would have 

excluded them from per protocol analyses, effectiveness was 60% (5, 85) and confidence 

intervals were significant. Another post-hoc analysis from the CAPiTA trial among the same 

population looking at all clinical CAP and not just the x-ray confirmed as in the original trial 

showed close to 62% effective (18, 83).1, 2 The test negative design study that is nested in the 

Louisville Cohort pneumonia surveillance presented previously to ACIP has demonstrated 

effectiveness of close to 53% (-100, 89) against ST3 CAP, but the confidence interval is very 

wide from that study3 [

1Bonten MJM, et al. NEJM. 2015; 2Gessner et al. In press; 3McLaughlin 

JM, et al. Clin Infect Dis. 2019].

The Louisville study demonstrated a 13% (8.5, 18.7) reduction in all-cause CAP and a 31% (8.3, 

48.9) reduction in PCV13-type CAP.1 From the same population with a shift in the timeline, 

although covering the same respiratory season from October 2014 to September 2015 as 

opposed to June 2014 to May 2015, the proportion of ST3 disease out of all-cause CAP was 

0.78%.2 In the same time period in the following year, the proportion of all-cause CAP that was 

ST3 was reported as 1.26%. These percentages were applied to the incidence of all-cause 

CAP, which results in 19/100,000 for ST3 CAP incidence in the October 2014 to September 

2015 timeframe and 26.2/100,000 in the October 2015 to September 2016 timeframe. That was 

in a setting of about 36% PCV13 coverage.3 Even though there was a reduction in PCV13-type 

CAP reported, there does not seem to be the same trend for ST3 incidence in the same 

population. A back of the envelope calculation relates to what is seen in IPD in which there may 

be some effectiveness, but no impact is seen at a population level. The calculation is: Expected 

incidence through direct effects in 2016 = (Incidence at baseline) x (VE) x (Coverage) = 18.8 x 

61.5% (VE) x 35.6% (Coverage) ≈ an incidence of 14.7 cases/100,000 in a setting of this level 

of coverage. However, a level of 26.2 cases/100,000 is being observed [1 Swerdlow et al June 

2018 ACIP pneumococcal session presentation; 2 Courtesy of Pfizer, unpublished data; 3

Estimated by applying %ST3 to all-cause CAP incidence].

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To summarize what has been observed in children in terms of PCV13 effectiveness against ST3 

IPD, there are inconsistent findings with most studies showing no effectiveness. The duration of 

protection may be shorter for ST3 than for other vaccine serotypes. At least a couple of 

comparisons in the literature, including the study highlighted for the US, suggest that toddler 

doses may be working better than infant series followed by a toddler dose. There is no

population-level impact on ST3 IPD demonstrated in the US and countries using PCV13. What 

is known for adults in terms of PCV13 effectiveness against ST3 IPD is that non-statistically 

significant VE was shown in a CAPiTA post-hoc analysis, although that study was not powered

to look at St#. The case-control study in the US was powered to look at ST3 and showed low 

and non-significant effectiveness. No population-level impact on ST3 IPD has been 

demonstrated in the US and countries using PCV13 among adults, indirect or direct. PCV13 

effectiveness against ST3 pneumonia in adults, moderate and non-significant effectiveness 

against ST3 CAP was found among adults in 2 Pfizer supported studies (CAPiTA and Louisville 

TND). Significant effectiveness was demonstrated in a post-hoc and modified ITT analysis of 

CAPiTA. From the limited data on the population-level impact on ST3 pneumonia, there is no 

evidence of impact in one cohort study by 2016 in a setting of approximately 36% coverage.

In conclusion, PCV13 may provide some level of direct protection against IPD and pneumonia 

caused by ST3. There are inconsistent findings across studies and populations, and 

effectiveness is lower as compared to other PCV13-types. Given the VE measured, the point 

estimates, and PCV13 coverage to date, some population-level impact is expected. However, 

no evidence has been seen of population-level impact on type 3 disease to date. That could be 

due to limited duration of protection or the fact that there is no impact on carriage, which means 

that there is continued circulation and exposure in the community. With a sufficient number of 

susceptible individuals being exposed, this may lead to the disease rate persisting. A high-level 

of uncertainty remains in terms of the expected benefits of PCV13 against ST3 disease. 

Therefore, the WG felt that the assumptions around inputs for VE against ST3 disease for 

models estimating expected public health benefits from PCV13 use in adults should consider a 

range of values, which ranges from no effectiveness (VE=0%) to account for studies with 95% 

CI for VE cross the null value to point estimates for VE against ST3 IPD and pneumonia that 

does assume some effectiveness. Some of these ranges can be seen in some of the analyses 

presented later in the session.

Discussion Points

Dr. Gravenstein wondered whether there is any other way to assess attenuation of disease; for 

example, if there is some residual benefit with ST3. One way to do that might be to examine 

cost. There is a cost profile for Medicare beneficiaries, which could be assessed to determine 

whether even if patients got pneumonia perhaps they had fewer hospital days or some other 

unmeasured effect.

Dr. Pilishvili indicated that they could look through the CMS data and IPD data for hospitalized 

cases to examine the impact of severity.

Dr. Stephens requested further elaboration on the difference between the earlier US and 

German studies that showed significant effectiveness versus the ones that show little 

effectiveness.

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Dr. Pilishvili replied that the schedule is one of the hypotheses that has been raised. In terms of 

the populations in the studies presented, for the studies that did not reach statistical 

significance, it was clear that they were able to look at the schedule with 2 infant doses followed 

by a booster. There were no significant findings from those studies. From the 2 studies that 

reported significance, she could speak clearly only for the US which was clearly a very different 

population from the UK study because of the transition between PCV7 and PCV13 vaccine. 

Most of the children in that group were immunized with a toddler schedule. That has been 

raised as a hypotheses, but she did not think there were a lot of data to support that.

Referring to slide 12 pertaining to the EU network study, Dr. Bernstein pointed out that between 

2011-2014 in the PCV13 countries, the vaccine seemed to be having a positive effect on ST3 

and then declined. He requested further information about the explanation for those 4 years.

Dr. Pilishvili indicated that the investigators explained it as probably being due to some natural 

variations. Initially, they attributed it to vaccine use and indirect effects when the initial findings 

were reported. Now that they see an increase, they have attributed it to natural variation in ST3 

incidence that coincided with the trends they were evaluating. The data shown for the US 

seems to suggest that there is variation every so many years. If two time periods in the US data 

were compared pre/post vaccine, it would be attributed to the vaccine and measure it as a 

vaccine impact. The longer term trends seem to suggest that the disease already was on the 

decline, making it harder to attribute the decline to the vaccine.

Dr. Bernstein asked whether it would be expected to mirror what is being seen in countries 

using PCV10.

Dr. Pilishvili indicated that countries using PCV10 did see more consistence increases, but the 

confidence intervals are very wide so it cannot be said with confidence that this related to the 

vaccine.

Effectiveness of PCV13 in Adults Hospitalized with Pneumonia 

Using Centers for Medicare & Medicaid Services Data, 2014-2017

Fernanda C. Lessa, MD, MPH 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Lessa presented on an analysis CDC performed in partnership with Acumen and CMS to 

evaluate the impact of the new PCV13 introduction in adults on pneumonia hospitalizations. She 

first acknowledged the Acumen team, who is a CMS contractor, and her CDC co-worker Trey 

Spiller for their dedication and commitment to this complex analytical project over the last 8 

months.

The project goal was to evaluate the direct effect of PCV13 on pneumonia hospitalizations 

among persons ≥65 years of age given the new PCV13 recommendation among US adults. To 

address the project objective, CMS Medicare Parts A/B data were used. The study cohort 

included all Parts A/B beneficiaries who were 65 years of age and older on September 1, 2014. 

After September 1, 2014, only beneficiaries who enrolled in Parts A/B within 6 months of their 

65th birthday were included in the cohort. Beneficiaries were observed until December 31, 2017 

unless they died, moved out of the US, dis-enrolled from Parts A/B, or developed the outcome 

of interest before the end of the observation period. Pneumococcal vaccination status was 

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divided into four categories: PCV13 only, PPSV23 only, both vaccines, or no pneumococcal 

vaccine.

Inpatient, outpatient, and physician Part B claims data were used to stratify the CMS Parts A/B 

beneficiaries into four mutually exclusive risk categories based on their underlying conditions 

and according to the previous risk-based pneumococcal vaccine recommendation for adults. 

The four mutually exclusive groups were High Risk 1 (HR1) only, High Risk 2 (HR2) only, both 

High Risk 1 and High Risk 2 (Both), and Low Risk. The most prevalent conditions for HR1 were 

CKD, generalized malignancy, and immunodeficiencies. The most prevalent conditions for HR2 

were chronic heart disease, chronic lung disease, and diabetes, with special attention to 

diabetes and chronic lung disease for which the prevalence was around 42% in the CMS 

Medicare Parts A/B population. Therefore, those individuals in the HR1+HR2 conditions are 

likely to be those with diabetes and CKD or chronic lung disease with iatrogenic 

immunosuppression.

Three outcomes were evaluated based on inpatient claims: 1) CAP, which was defined based 

on discharge codes and a previously published algorithm by Griffin and colleagues; 2) nonhealthcare associated CAP, which was defined as a CAP in a patient without an admission to a 

hospital or skilled nursing facility in the 30 days prior and without a prior healthcare-associated 

pneumonia hospitalization; and 3) lobar pneumonia, which was defined as discharge codes of 

lobar/pneumococcal pneumonia in any discharge position.

A discrete time survival model was used to calculate instantaneous hazard ratio, which is 

equivalent to incidence rate ratio (IRR). The outcome of interest was treated as a binary variable 

in each month of the study period. Generalized estimating equations (GEE) was used to adjust 

for correlations with the assumption of proportional hazard. VE was calculated as 1 minus the 

IRR multiplied by 100.

Four separate models were created that were stratified by influenza season and influenza 

vaccination status. Influenza season was defined as the months of October through April, while 

non-influenza season was the months of May through September. The rationale for the four 

models was related first to concerns with biological interaction between influenza vaccine and 

secondary bacterial pneumonia, including pneumococcal pneumonia. Second, the availability of 

current data showing that pneumococcal and influenza vaccines are not an independent 

observation. PCV13 coverage goes up during the period that influenza vaccine is available.

Third, the current published influenza literature showing that underlying characteristics of 

influenza-vaccinated individuals are different compared to influenza-unvaccinated individuals.

Each of the four models was adjusted for the following variables: 

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Age group (5-year bands)

High risk condition category

State

Race

Gender

Hospital visits in prior year

Outpatient non-ER visits in prior year

Charlson comorbidity index 

Reason to enter CMS (Age, ESRD, Disabled, other) 

Month of year (e.g., January, February)

Year 

Interactions: vaccine and age group, vaccine and risk group, age and risk group

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These variables represent potential confounders related to immunization practices; for example, 

states with high incidence of CAP may have higher rates of PCV13 administration. Confounders 

related to selection bias on who receives the vaccine also were adjusted for; for example, older 

and sicker persons may be more likely to receive PCV13 compared to younger and healthier 

adults.

To calculate the number of hospitalizations averted, the number of hospitalizations for each 

outcome was first estimated in the absence of PCV13 using the observed number of episodes 

divided by the IRR based on model results, and then subtracted this expected number in the 

absence of PCV13 by the number of observed episodes.

At the beginning and end of the cohort, there were 26.5 million and 24.1 million beneficiaries 

≥65, respectively. This represents approximately 57.6% of the US ≥65 population. Around 55% 

of the cohort was comprised of individuals 65-74 years of age. Despite the study design to only 

allow persons who enrolled in CMS Parts A/B within 6 months of their 65th birthday after the 

beginning of the study, the age distribution did not change from the beginning to the end of the 

cohort. Male distribution was similar at the beginning and the end of the cohort. PCV13 use 

increased from 0.8% at the beginning of the cohort to 41.5% at the end of our cohort. In terms of 

the high risk categories, the distribution was similar at the beginning and at the end of the 

cohort, with the HR1 only category being rare at about 5%. Most of the cohort were represented 

by either HR2 only or HR1+HR2. Also, over one quarter of the CMS Parts A/B beneficiaries had 

severe underlying conditions as represented by the Charlson Index and frequent healthcare 

exposure.

In terms of the characteristics of the beneficiaries who got PCV13 based on the last month of 

the study period, PCV13-vaccinated individuals tended to be older, sicker, with more contact 

with the healthcare setting, and substantially more likely to have received influenza vaccine 

compared to PCV13-unvaccinated adults. The average of CAP incidence across the study 

period was 148/100,000 person months. Non-healthcare-associated CAP is a subset of CAP 

and the average incidence was 115 per 100,000 person-months. Lobar pneumonia was 

relatively rare with an incidence of 6/100,000 person months. CAP incidence varied by age 

groups ranging from 86/100,000 person months for the age group 65-74 years to 334/100,000 

person months for the age group 85+. CAP incidence also varied greatly by risk group. Those 

who had HR1 + HR2 condition had a CAP incidence almost 3 times higher compared to HR2 

only and 14 times higher compared to the low risk group.

Moving to the model results, it is important to bear in mind the characteristics of the 

beneficiaries in each model in order to understand the PCV13 VE results. The influenza season 

models had the largest number of total person months compared to the non-influenza season 

models. The proportion of beneficiaries 65-74 years of age for the models with influenzavaccinated individuals was around 48%, while the models with influenza-unvaccinated 

individuals was 59%-62%. A similar pattern was seen in terms of the proportion of HR1+HR2 

and low risk. While the models with influenza-vaccinated individuals had 37% and 19% in the 

HR1+HR2 and low risk categories, respectively, the models with influenza-unvaccinated 

individuals had 28% of the individuals in HR1+HR2 and approximately 33% in the low risk 

group. Therefore, the models with influenza-unvaccinated individuals represent a heathier group 

of elderly compared to the models with influenza-vaccinated individuals.

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In terms of PCV13 VE against all-cause CAP across the four models, the VE point estimate 

ranged from 6% in the influenza season/influenza-vaccinated to 11.4% in the influenza

season/influenza-unvaccinated. Regarding PCV13 VE against non-healthcare associated CAP 

across the four models, the VE point estimate ranged from 5% in the influenza

season/influenza-vaccinated to 11.0% in the influenza season/influenza-unvaccinated. For 

PCV13 VE against lobar pneumonia, the VE point estimate ranged from 1.3% in the influenza

season/influenza-vaccinated to 11.0% in the influenza season/influenza-unvaccinated model.

Based on these analyses, PCV13 averted 28,600 CAP hospitalizations, which includes 18,700 

non-healthcare associated CAPs, and 1100 lobar pneumonia hospitalizations from September 

2014 through December 2017. Of the 28,600 CAP hospitalization averted, 18,700 were averted 

during the last year of our study period from January to December 2017. The reason for most 

CAP hospitalizations to be averted in the later years is probably related to change in the risk 

distribution of the individuals who are getting the vaccine as PCV13 coverage goes up over 

time. The proportion of low risk individuals who are getting PCV13 only and for both PCV13 + 

PPSV23 increased between 2014 and 2017. This is likely the group who will benefit the most 

from the vaccine.

The study has several limitations. Despite all of the adjustments, all the biases inherent to 

administrative data probably were not eliminated. It has been shown that ICD codes fail to 

remove all confounding in pharmacoepidemiologic studies among seniors. A major problem is 

the lack of reliable ICD codes to measure functional status. The adjustments made for chronic 

conditions and healthcare utilization can reduce biases, but do not completely eliminate them.

Also, based on the experience from the hospitalized influenza VE network and the ABCs 

surveillance, up to 30% of the individuals who had documentation of influenza or PPSV23 

according to active surveillance were misclassified as unvaccinated in CMS data.

Misclassification was uncommon for PCV13 vaccination status when ABCs data was compared 

to CMS data.

In summary, CAP incidence is highest among individuals ≥85 years of age and those with 

HR1+HR2 conditions. Individuals who got PCV13 were older, sicker, and had more healthcare 

exposures compared to those who were unvaccinated. Effectiveness of PCV13 was observed 

against first episode of CAP, non-healthcare associated CAP, and lobar pneumonia.

In conclusion, VE for PCV13 against all-cause CAP ranged from 6.0% to 11.4%, which is similar 

to what Gessner and colleagues published using clinical trial data from the Netherlands in the 

CAPiTA trial. Based on this analysis, approximately 28,600 CAP hospitalizations were 

prevented within 40 months after the implementation of the new adult PCV13 program. Of 

those, 65% or 18,700 were prevented in the last 12 months of the study period. The large 

proportion of cases averted in 2017 is likely related to the changes in the characteristics of the 

individuals who are getting PCV13 in more recent years. However, it is important to note that 

this number of cases averted represented only 5.1% of all-CAP hospitalizations in 2017.

Discussion Points

Dr. Gravenstein observed that it was a very complicated process to try to adjust for an 

unhealthy population and compare them to others, especially when working with Medicare 

claims. He suggested that when looking at hospitalizations as an outcome, risk adjusting for 

prior hospitalizations might be a more effective strategy than just using disease categories. 

While the focus was specific to CAP, pneumonias also cause other outcomes. For example, 

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30% of hospitalized pneumonias also relate to cardiac events. That might be another outcome 

of interest that could be prevented with pneumococcal vaccination.

Dr. Lessa indicated that the number of hospitalizations in the prior year was adjusted for in this 

model. She thought perhaps what he was suggesting was that they could exclude those who 

had hospitalizations the prior year.

Dr. Gravenstein said he was thinking of a prior event rate ratio as a specific approach.

Dr. Lessa indicated that they could look at other outcomes as well.

Dr. Bernstein pointed out that obesity plays a role in influenza disease as a high risk condition, 

and he wondered whether they have found the same in IPD or pneumonia.

Dr. Lessa indicated that they did not look specifically at obesity for this particular analysis, but it 

is a good point.

Dr. Stephens requested further information to sort out the effect between PPSV23 versus 

PCV13 in this analysis in terms of whether they are getting both vaccines, and if anything could 

be said about the efficacy of polysaccharide alone.

Dr. Lessa said that although she did not present those data, they did assess this. The way they 

looked at it may not have been the most appropriate way, because there is a waning effect of 

PPSV23. Their analysis included anyone who received PPSV23 in the last 5 years. The other 

thing they have found with this analysis is that the PPSV23 patient population is extremely sick. 

They know from the influenza study that it is important to adjust for functional status, but they 

were not able to do that for this analysis. When PPSV23 was compared to unvaccinated, no 

effect was seen. But again, she did not think the way they looked at this was the most 

appropriate way for PPSV23.

Dr. Szilagyi asked what percentage of all CAP were from the Low Risk group, and clarification 

that they were surmising that the increase in vaccination rates among that population might 

have accounted for some of the results even though they were unlikely to be hospitalized with 

CAP.

Dr. Lessa replied that the incidence among the Low Risk group is lower overall. In terms of 

overall VE with stratification of the HR groups, VE is higher among the Low Risk group.

Dr. Messonnier indicated that VE was stratified across the 4 models for PCV13 only compared 

to unvaccinated. The groups were HR1 + HR2 and HR2 only, and Low Risk. Across all of the 

models, even though the Low Risk group had a large confidence interval and the person months 

are small in this group and they have a lower number of events, they had a higher VE compared 

to the HR1 + HR2 and HR2 only.

Dr. Rockwell (AAFP) observed that as an outpatient family physician, this raised more questions 

than answers for her. Those in the Low Risk group who are least likely to be hospitalized do get 

diagnosed with pneumonia and get treated and get better. However, all of them who might 

benefit from the vaccine are not being captured. 

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Overview of Three Economic Analyses of Pneumococcal Vaccinations at age 65

Andrew J. Leidner, PhD 

Health Economist & ACIP Economics Lead 

Berry Technology Solutions Federal Contractor for: 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Leidner indicated that this presentation would describe three cost-effectiveness models 

developed by three different teams: CDC, Pfizer, and Pittsburgh. A presentation and report for 

each model were given to the ACIP Pneumococcal Vaccines WG. All three reports went through 

the CDC economic review following the ACIP Guidance for Health Economics Studies. 

Completion of the economic review does not confer any explicit or implied approval of the 

model. The study question was, “Should PCV13 be administered routinely to all 

immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV 

use experienced to date?” The cost-effectiveness ratios (CERs) from the three models 

compared two scenarios: PCV+PPSV at age 65 years, which is the current recommendation, 

versus PPSV-only at age 65 years.

Beginning with the CDC model, the current CDC base case estimates that the cost per QALY is 

$562,000. This an adjustment from the $649,000 estimate presented in October 2018 in that 

two parameters were updated, VE and case fatality ratios (CFRs). In a sensitivity analysis with a 

higher VE-PCV(ST3), the cost per QALY was $222,000. This scenario turned out to be a very 

important parameter in the models. The Pfizer base case estimate is $199,000 per QALY. An 

alternate base case that included immunocompromised was $186,000. For the purposes of this 

summary presentation, the focus was on the scenario that excludes immunocompromised 

because the policy decision is more focused on the immunocompetent population and also 

brings the Pfizer scenario in closer alignment to what was used in the CDC model. The 

Pittsburgh model, the base case cost-effectiveness estimate is $765,000 per QALY. The 

Pittsburgh model was designed to investigate differences in Black and non-Black populations for 

which the cost per QALY is $814,000 and $761,000, respectively. For the purposes of 

comparability to the other models, the primary focus for this session was the total population.

Relative to the CDC model, the Pfizer model has: 1) higher VE-PCV assumptions most 

importantly the assumption against VE-PCV(ST3); 2) more severe case assumptions, meaning 

that there is a higher QALY loss per case and higher CFRs; and 3) lower indirect effects from 

childhood vaccination on older adults. The Pittsburgh model has: 1) higher VE-PPSV 

assumptions, which is one of the main reasons that this model estimate is higher than the other 

two estimates in the base case; 2) no indirect effects, making it slightly less comparable to the 

other two; and 3) more detailed modeling of Black and non-Black populations.

Regarding a few of the most important modeling assumptions, for indirect effects the CDC 

model assumes a 4.1% decline in incidences that are affected by the indirect effects every year 

until the model ends. The Pfizer model assumes 4.1% as well, but only for the first 3 years of 

the model. The Pittsburgh models includes no indirect effects. For utility loss for IPD and utility 

loss for inpatient pneumonia, the Pfizer model assumptions are higher than the CDC model and 

the Pittsburgh model. The CDC model has the lowest assumptions. The Pfizer model has higher 

case-fatality ratios for inpatient pneumonia than the CDC and Pittsburgh models.

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The Pfizer model assumes about 10% more VE-PCV (non-ST3) pneumonia in the first 5 years 

of the model, and they both converge to 0% after 20 years. For ST3 disease, the Pfizer model 

assumes the same thing it did in the non-serotype 3 case of about 40% for 5 years and then 

declining. The CDC model assumed 0% effectiveness in its base case for ST3 pneumonia. In 

the sensitivity analysis mentioned earlier, CDC had Higher VE (ST3), this assumption is 

increased to about 45% for 5 years and then it declines. The story is similar with IPD. The Pfizer 

model assumes about 10% more VE for non-ST3 IPD in the first 5 years, then the Pfizer and 

CDC models converge to 0% at age 85. The Pfizer model assumes a base case of 26% VE for 

the first 5 years for ST3 IPD and then declines, and the CDC model assumes 0% in the base 

case. In the sensitivity analysis in which the CDC model has higher VE ST3, the CDC 

assumption is the same as the Pfizer assumption for IPD.

To try to confirm what is thought to be occurring based on the differences in the assumptions, 

some of the results will be examined. Beginning with health outcomes, comparing the within 

model in-patient IPD burden averted, the inpatient pneumonia cases are much higher in the 

CDC and Pfizer models. Therefore, inpatient pneumonia is more important than IPD. The story 

is similar for averted deaths in that a greater number of deaths are predicted in all 3 models due 

to pneumonia as opposed to deaths due to IPD. In terms of QALYs gained in each of the 

models, Pfizer has the highest number due to a higher QALY loss estimate assumption per 

case, a higher CFR per case, and higher VE which averts more cases.

Moving to a more detailed look at some of the CERs, the Pfizer model assumes the CDC 

assumptions on VE-PCV in which the CER goes from about $200,000 per QALY to about 

$590,000 per QALY. This increase is due in most part to ST3 pneumonia and at least in part to 

ST3 IPD. The second most important category is non-ST3 IPD and pneumonia. The mirror 

image of that exercise done from the CDC model perspective in which the CDC model assumed 

a higher VE against ST3 brings it closer to, but not exactly the same, as the Pfizer VE 

assumptions. The base case CER now declines to $222,000 per QALY, putting it very close to 

the Pfizer base case estimate. By imposing the CDC assumptions for indirect effects, utilities, 

and CFRs on the Pfizer model base case, the CER estimate increases but not quite as 

dramatically as when VE was changed. When the Pfizer model assumptions on indirect effects, 

utilities, and CFRs were imposed on the CDC base case, the CERs declined. The largest 

decline was in CFR, but not as much as when the different VE assumptions were imposed.

Regarding the one-way and multi-way sensitivity analyses, the CDC and Pittsburgh models had 

a lot more variability and uncertainty in their outcomes than the Pfizer model. The extreme 

points in the CDC and Pittsburgh models were when they assumed a relatively high level of VEPPSV against PPSV-type pneumonia of 45%. The lowest CER in the studies for one-way and 

multi-way analyses was in the Pfizer study, which assumed a relatively high VE-PCV against 

PCV-type pneumonia of 73%, higher PCV-type pneumonia incidence, and higher PCV-type 

pneumonia CFR.

In conclusion, VE appears to be the most important assumption in these models, especially VE 

of PCV against serotype 3 pneumonia. There were varied assumptions on VE for PCV and 

PPSV across all of the models. Other important assumptions were indirect effects, utility loss 

per case, and CFRs. The models assume different levels of uncertainty, with the Pfizer model

having the least amount of uncertainty. The base case values ranged from about $200,000 to 

$765,000 per QALY averted. In the full range, the base case values ranged from about $46,000 

per QALY averted to over $2 million per QALY averted.

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Manufacturer Response

Dr. Luis Jodar 

Chief Medical Officer 

Pfizer Vaccines 

Dr. Luis Jodar read the following statement into the record:

We are all here today trying to do the best for patients and for public health. PCV13 has already 

prevented thousands of hospitalizations and deaths in people 65+ in the United States. I think 

we all agree that we have a proven safe and effective vaccine against both IPD and communityacquired pneumonia caused by the 13 pneumococcal serotypes in the vaccine, including 

serotype 3. For this reason, and although today it has been moderated, Pfizer cannot agree with 

CDC’s assigned value of zero for PCV13 vaccine efficacy, not effectiveness, efficacy against 

serotype 3 community-acquired pneumonia as the base case scenario for the cost-effectiveness 

model. It has been argued that this is a question of difference of opinions, or a different 

interpretation of the data. Pfizer argues that this is not a question of opinion, but a question of 

facts. I would like to review very quickly the data that Dr. Pilishvili has very eloquently reviewed 

for you on serotype 3. As you remember, CAPiTA, which is a randomized controlled efficacy 

trial among 85,000 adults aged 65+, served as the pivotal trial to confirm PCV13’s indication 

against vaccine-type community-acquired pneumonia. This should be the primary source of the 

data for all of the estimations. Dr. Pilishvili mentioned, and she was right, that none of these 

trials were unfortunately powered to measure serotype-specific vaccine efficacy. However, in 

the modified intent-to-treat analysis, or mITT, vaccine efficacy against serotype 3 was 60% with 

confidence intervals from 5% to 85%. This result was submitted to the FDA in January 2015. 

Based on this analysis, the base case for serotype 3 just cannot be zero. Now, you did not see 

the data in the handouts, but I appreciate that Dr. Pilishvili included these mITT data in today’s 

CDC presentation.

However, I do not think that that is yet recognized the CDC cost-effectiveness analysis. It is 

important to note that in the CDC cost-effectiveness analysis, the model used the CAPiTA mITT 

for all of the other parameters with the notable exception of serotype 3. As we have seen, had 

the CDC used the serotype 3 analysis as the base case in their model, the results would have 

been dramatically different. Dr. Pilishvili, in the summary tables, presented a different analysis, a 

post-hoc analysis, different from the mITT that I just mentioned. Just to be clear, that post-hoc 

analysis, which was also derived from CAPiTA, included all clinical community-acquired 

pneumonia regardless of the radiographic outcome. As shown in her presentation, the vaccine 

efficacy against serotype 3 was also high at 62% with confidence intervals from 18% to 83%, 

which supports the basic mITT analysis that I mentioned before. She mentioned also the 

Louisville data. There could be a debate about the epidemiological robustness or not, but when 

we pooled the data from serotype 3 for CAPiTA and the only other two adult test-negative 

design studies conducted so far, because Dr. Pilishvili did mention that yes Pfizer has the UAD 

which is validated by the FDA to measure serotype-specific, when you pool all of that data 

together, we showed a vaccine combined efficacy of 53% with confidence intervals from 6% to 

76%. Again, this reaffirms that PCV13 provides a substantial level of protection against serotype 

3.

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The second point that I want to emphasize today, because it was emphasized a lot here, is 

related to the surveillance population, the population impact data, which I think is a little bit more 

debatable. So, I agree with Dr. Pilishvili. It is true that serotype 3 has not gone down in the US. 

However, in countries that have not introduced PCV13, rates of serotype 3 in adults have 

notably increased. People have asked, “Well, I mean in the European Union you see a 

decrease in your data and then a slight increase, and in other countries a sustained increase, 

and it has been argued that these might be natural variations. Well, it is almost like there is an 

epidemiological conspiracy to get the same results in all of the countries that use PCV13 versus 

the countries that use other vaccines. What we have seen in all countries, and if you look at all 

surveillance studies, is that yes it goes down, and I think you explained it very well about 

coverage—it goes down and then starts to level, and then perhaps it slightly increases, with a 

difference in other countries that it is steadily increasing. What is more important is in countries 

that have a PCV13 program but no other program, and I’d like you to look at the UK and 

Germany, serotype 3 has dramatically increased in adults. The data suggest that a similar trend 

can be expected in the United States if the adults 65+ vaccination recommendation is removed. 

So, with all of this as a background, a key question for the entire community is, “Will taking this 

recommendation away lead to unnecessary hospitalizations and deaths from serotype 3 and 

from the other 12 serotypes in the vaccine?” Based on the data showing PCV13 direct efficacy 

against serotype 3 and given the surveillance trends that we are seeing elsewhere, we judge 

the answer is “yes.” Thank you very much.

Discussion Points

Dr. Lee thanked Dr. Jodar for the scientific input on behalf of the Pneumococcal WG and ACIP. 

They are thankful for the impact that PCV13 as a product has had on overall disease burden in 

the US in both children and adults. With due respect to those comments, she said she wanted 

to pull them back a step because she felt like the bigger issue regarded thinking about the main 

issues related to disease burden. She does think the models are all very sensitive to VE, and 

perhaps what did not come across was that the CDC model was conservative on both serotype 

3 VE and PPSV23 VE. Both were assumed to be zero. There is uncertainty on both of those 

estimates, so having a range of sensitivity analyses is incredibly important, but she thought it 

perhaps should be applied to both estimates. Applying it only to one and only to the other 

provides the two extremes since it seems like the Pittsburgh model had some PPSV23 

effectiveness and no serotype 3. Conversely, the Pfizer model had serotype 3 effectiveness but 

no PPSV23. The CDC model happened to be in between.

Speaking from an outpatient perspective, Dr. Rockwell point out that the reality of publishing a 

complex recommendation such as, “All adults 65 and above should receive PCV13, and it 

needs to be in this order with this amount of time in between PPSV23, and it should be repeated 

if you do it wrong . . .” is that it takes more than a year to get that enacted, if not longer. In fact, it 

still may not always be done correctly. She wondered if they knew from the data how many of 

these adults actually get these vaccines in the correct order and if that was accounted for 

correctly, and if perhaps the data were being assessed prematurely since there has not really 

been sufficient time to look for longer trends if, in fact, the trends from other countries are 

showing different results.

Dr. Messonnier recalled that coverage data have been presented in previous meetings and they 

could share the data again, and she agreed that it is complicated and the answer is probably not 

one number.

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Dr. Pilishvili added that they have examined this at the population level and as part of the 

special studies that have been presented on effectiveness and efficacy for the CMS population. 

She thinks it is a combination of elements, such as the order in which vaccine was received. 

This is related to the fact that when the recommendations were made, there already was a large 

cohort of adults who had received polysaccharide vaccine. For newer cohorts, they do see the 

correct order. To what extent that occurs is hard to assume, because the surveillance data they 

have that tracks coverage does not have the power to assess the order in which the doses are 

received. That is a limitation.

Dr. Szilagyi said that while he understood that the models were most sensitive to VE, he was 

unclear about the large difference across the models in the utilities and wondered what they 

were based on.

Dr. Leidner explained that there were 3 different assumptions on utility. The CDC model used 

more or less research standard values from a 1993 survey in Massachusetts. The Pittsburgh 

model took a more expert opinion-like approach, but also used values that have been used 

several times recently and assumed a fixed level of utility of 0.4 if one was hospitalized and that 

hospitalization would last about a month. That is a standard assumption. The Pfizer model came 

from a sub-study of CAPiTA in which individuals who ultimately got pneumonia were matched 

with other individuals in the cohort who did not get pneumonia, and they compared the 

differences in utilities over a year across those two groups. It is a very new study, so it has not 

been used as widely in the literature thus far.

EtR and GRADE for PCV13 Use Among Immunocompetent Adults ≥65 Years Old

Almea Matanock, MD, MS 

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Matanock summarized the EtR and GRADE evidence for PCV13 use among adults ≥65 

years old in the setting of sustained indirect effects. As a reminder about the current adult 

recommendations for pneumococcal vaccines, in 2012 ACIP recommended PCV13 in series 

with PPSV23 for adults 19 years and older with an immunocompromising condition. This 

recommendation is not being reconsidered at this time. In 2014, ACIP recommended PCV13 in 

series with PPSV23 for all PCV13-naïve adults ≥65 years with the following considerations. The 

committee thought that the short-term use was warranted because of the remaining PCV13-type 

disease burden. However, it was thought at the time that the long-term utility may be limited due 

to anticipated indirect effects from pediatric PCV13 use. Therefore, ACIP proposed that the 

recommendations for routine PCV13 use among adults ≥65 years old be re-evaluated in 2018 

and revised as needed, which led to this session.

The current policy question is, “Should PCV13 be administered routinely to all 

immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV 

use experienced to date?” The population is immunocompetent adults ≥65 years of age, with 

and without chronic medical conditions. The intervention is PCV13 at 65 years and older 

followed by PPSV23, in the context of indirect effects. The comparison is PPSV23 alone as that 

was the recommendation before this was enacted in 2014. The outcomes for this evaluation 

were IPD, pneumonia, mortality, and PCV13 safety. To evaluate this question, the ACIP EtR 

Framework was used. 

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First to put things into context, Dr. Matanock reviewed what is known about the indirect effects 

from pediatric PCV use. From the time of first introduction of PCVs in 2000 to 2014, there was a 

9-fold reduction in PCV13-type IPD amongst adults ≥65 years of age. Two-thirds of this 

reduction was in the first decade after PCV7 introduction. At the time PCV13 was recommended 

for older adults in 2014, there had been a 3-fold decrease in IPD from PCV13 use alone.1 What 

was not known in 2014 is what the continued indirect effects would be. Since 2014, there has 

been a plateau in PCV13-type IPD. What has been observed in the US is similar to what other 

European countries have observed in terms of PCV13-type disease amongst older adults2

[

1Active Bacterial Core Surveillance, https://www.cdc.gov/abcs/reports-findings/survreports.html, comparing 2000 to 2014; 2Hanquet et al. 2018].

In terms of the indirect effects from pediatric PCV use on pneumonia among older adults, most 

studies have demonstrated a decline in all-cause pneumonia since the introduction of PCV7 in 

2000.1In the UK, where they are able to measure non-invasive pneumococcal pneumonia using 

an SSUAD, they observed a decrease of 88% in PCV7-type pneumonia and an additional 

decline of 30% in the PCV13 unique serotypes after PCV13 introduction in 2010.2In the US 

since pediatric PCV13 introduction, pneumococcal pneumonia hospitalizations have declined. 

Dr. Lessa’s June 2018 presentation to ACIP showed declines in pneumococcal pneumonia for 

adults with the exception of adults 75 years and older where the credible intervals of the 

synthetic control model crossed one3[

1Tsaban et al. 2017, 2Rodrigo et al. 2015, 3Lessa ACIP 

October 2018].

Additionally, for context presented here is the coverage for pneumococcal vaccines among 

Medicare beneficiaries aged 65 years and older. In 2016-2017, approximately 40% of older 

adults had received at least one dose of PCV13. Included in this number are the 24% who 

received both PCV13 and PPSV23; that is, those who had completed the recommended 

schedule of pneumococcal vaccines [https://www.cdc.gov/vaccines/imzmanagers/coverage/adultvaxview/pubs-resources/pcv13-medicare-beneficiaries.html].

PCV13-type IPD incidence has plateaued at 5/100,000 among adults ≥65 years. The remaining 

PCV13 serotypes account for 20% of all IPD plus an additional 3% when including 6C, a 

serotype not included in PCV13 but for which there is cross-protection. The most common 

PCV13 serotypes are 3, 19A, 7F, and 19F with 3 accounting for 66% of the remaining PCV13-

type IPD in 2017. As discussed before, PCV13-type pneumonia incidence is more difficult to 

measure. The US-based serotype-specific incidence comes from Pfizer’s Louisville study. The 

incidence measured in Louisville was 76/100,000 in the most recent year of the study, 2015-

2016. The incidence presented by Dr. Lessa presented earlier in the session is close to this 

estimate from Louisville at 73/100,000 in 2015. Using the Surveillance for Non-invasive 

Pneumococcal Pneumonia (SNiPP), non-invasive pneumococcal pneumonia estimates results

in a much lower estimate of 17/100,000, which as Dr. Matanock presented in October 2018, is 

close to the other estimates in the literature of pneumococcal pneumonia incidence. Again, this 

is not just PCV13 serotype-specific. The estimate there though is applying the ratio seen in IPD 

to what was observed in SNiPP. In the most recent year of data from the Louisville study, 2015-

2016, serotype 3 was most common, accounting for 37% of all PCV13 types.

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Comparing the remaining PCV13-type disease burden among older adults to other vaccinepreventable disease for which there are vaccine recommendations for adults, PCV13 type 

pneumococcal pneumonia is less than that of zoster or influenza, for which there are universal 

recommendation for adults. PCV13 type pneumococcal pneumonia is greater than 

meningococcal serogroup B, for which the recommendation is based on individual clinical 

decision-making.

The WG perspective on the remaining burden of PCV13-type disease among older adults is that 

PCV13-type disease has been dramatically reduced through indirect effects, but some burden 

still remains in older adults. There is uncertainty about the burden of pneumococcal pneumonia 

and mortality associated with PCV13-type disease. Since the 2014 recommendation, no further 

reductions in IPD have been observed at the population level and inconsistent results from 

pneumonia impact studies. In answering the EtR question, “Is the PCV13-type disease burden 

still of public health importance?” the WG’s perspective was “Probably Yes.”

Now to look at the Benefits and harms using GRADE, just to remind everyone again that this is 

the policy question evaluated in GRADE, “Should PCV13 be administered routinely to all 

immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV 

use experienced to date?” In more detail, the outcomes of interest were: PCV13-type IPD, 

PCV13-type non-bacteremic pneumococcal pneumonia (NIPP), PCV13-type disease mortality, 

and SAEs associated with PCV13. The effect was evaluated by examining efficacy and 

effectiveness for individual-level effects associated with PCV13 use, and impact at the 

population level.

A systematic review was conducted of studies using Medline, Embase, CINAHL, Cochrane, and 

clinicalstrials.gov databases using search the search terms: (Pneumococcal Vaccin*) OR 

(pneumococcus vaccin*) OR (pneumonia* vaccin*) OR PCV13 OR pneumovax OR PPSV23 OR 

prevnar* OR pnu-immune AND senior* OR aged OR older adult* OR elderly OR (over 65) OR 

(older 65) OR >=65 OR =>65. Articles were reviewed from January 1, 2014 to July 3, 2018. 

Efforts were made to obtain unpublished or other relevant data, including presentations to the 

WG from industry and independent researchers.

For observational studies, studies were excluded with low PCV13 coverage in the population 

studied and in which the indirect effects would have been expected to be different than in the 

US population. For safety studies, studies were excluded in which PCV13 was co-administered 

with other vaccines since the SAEs in these trials could not be attributed to PCV13 alone. 

Additionally, RCTs were excluded in which there was no comparison to either PPSV23 or 

placebo. In the review process, 2239 title and abstracts were screened. Ultimately, 20 studies 

were GRADED after excluding studies that were in other population, had different outcomes 

than those in GRADE, or were examining pneumococcal vaccines other than PCV13.

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First to look at PCV13 efficacy, effectiveness, and impact on PCV13-type IPD, this table 

identifies the studies that were included:

The first two rows are the estimates from the CAPiTA study, a very large RCT looking at the 

endpoint of pneumococcal pneumonia. The first estimate is per protocol and the second is all 

episodes in a mITT analysis. The two are very close and significant at 75% (41, 91) and 76% 

(48, 89). The second two lines are two case-control studies, both using ABCs IPD cases but 

with different controls. The point estimates from these studies are slightly lower, but still 

significant, with confidence intervals that overlapping those from the CAPiTA. In the last row is 

what has been seen at the population level in terms of impact on PCV13-type IPD. At the 

population level, it is not possible to separate out direct from indirect effects, but a statistically 

significant change in PCV13 type IPD incidence has not been observed using the period just 

before PCV13 introduction for older adults to the most recent data available, 2016-2017.

Before moving on to the second critical outcome, PCV13-type pneumonia, Dr. Matanock went

through a schematic which she hoped would help to organize the various VE estimates

available for pneumonia:

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First for PCV13-type pneumonia including IPD, this table identifies the studies that were 

included:

The first two rows are the efficacy from CAPiTA. The second two lines are two case-control 

studies. McLaughlin et al is Pfizer’s Louisville cohort specifically using a nested case-control 

study to look at PCV13 effectiveness on pneumonia. Both of these estimates are statistically 

significant. In the observational study from Louisville, the confidence interval is both lower and 

higher than that seen in CAPiTA. There is one small study from Italy, Prato et al. This study did 

not use an SSUAD, so confirmed cases were from NP swabs, sputum, bronchial lavage (BAL), 

and other sterile site cultures. They had a non-significant estimate of VE. In the last row is the 

impact at the population level from the Louisville cohort for PCV13-type invasive and noninvasive pneumonia. At the population level, an impact is seen in this study in the two years that 

they used. Essentially, it is the first year of vaccine introduction when coverage was about 11%

compared to the second year when coverage was about 36%.

Next are estimates from two studies looking just at PCV13-type non-invasive pneumonia. The 

first from CAPiTA (Webber) and the second from Louisville (McLaughlin). From CAPiTA, there 

is a statistically significant VE. From Louisville, the confidence interval at the lower end crosses 

0 when excluding IPD.

Moving on to NIPP at the population level from surveillance for NIPP (Gierke), a statistically 

significant decline was observed between 2013-2014 versus 2015-2016. However, when the 

dramatic declines between 2013-2014 are not included and just 2014 is compared to 2016, 

there have been no declines.

And now at the base of the pyramid, PCV13 effectiveness against all-cause pneumonia. 

The first row is from CAPiTA (Gessner), which found an 8% VE against all-cause pneumonia in 

a post-hoc analysis. The second row is the range of estimates from the stratified analysis 

presented earlier by Dr. Lessa of 6%-11%. Both of these estimates are significant, but are lower 

because this is a less sensitive outcome. 

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PCV13-type disease mortality is the third critical outcome. There is very little information for this 

outcome. The first estimate is from CAPiTA (Bonten), which found 7% all-cause mortality in both 

the PCV13 and placebo arms over the course of the trial, but no VE against PCV13-type 

disease or all-cause pneumonia. Examining PCV13-type IPD mortality in ABCs comparing 

2013-2014 to 2016-2017, A significant change is not observed in mortality since the 2014 

recommendation was made.

With the burden of disease observed and the highest VEs from CAPiTA, every year roughly 

26,300 older adults would need to be vaccinated with PCV13 to prevent 1 case of IPD. For 

inpatient pneumonia, between 3,000 to 14,000 older adults would need to be given PCV13 to 

prevent 1 case of inpatient pneumonia. Approximately 2,600 older adults would need to be 

given PCV13 to prevent 1 case of outpatient pneumonia.

Since 2014, the WG identified 4 published RCTs that reported SAEs: Bonten 0.8%, Jackson 

2.3%, Juergens 0.6%, and Shiramoto 0.3%. Presented here is the total number of SAEs. 

However, it should be noted that in total these percentages represent very few SAEs, most of 

which were determined not to be related to the vaccine. In addition to the 4 RCTs, the WG

identified 5 observational studies, which observed similarly low rates of SAEs: Durando 0.1%, 

Haber ,0.01%, Shiramoto 0%, Tinoco 1.2%, and Tseng1.2%-5.8%. When the results of Haber 

and Tseng were presented to ACIP by Tom Shimabukuro in June 2018, the conclusion was that 

there were no new safety signals or unexpected patterns observed, providing reassurance 

regarding continued use of PCV13 amongst older adults. The WG’s conclusions after reviewing 

the literature remain the same.

To summarize GRADE, according to ACIP GRADE guidelines RCTs are initially given an 

evidence type of 1 and observational studies an evidence type of 3. The WG downgraded 

CAPiTA, the RCT, for the IPD outcome on indirectness because PCV13 was compared to 

placebo not PPSV23, which is the alternative in the policy question and for which there is an

established efficacy against IPD. The WG downgraded CAPiTA as well for the mortality 

outcome on imprecision, but it should be mentioned that this was not the primary endpoint and 

that there were very few deaths overall caused by PCV13-type disease (2 in both the 

intervention and control arms). The WG downgraded the case-control studies for the IPD 

outcome based risk of bias from potentially unmeasured confounding and misclassification of 

vaccine status and indirectness for impact studies which looked at population level effects. 

Additionally, for pneumonia among the observational studies, the WG downgraded the risk of 

bias because of non-specific measures of the outcome. There was inconsistency between study 

results, and among the impact studies not only were they looking at population level effects, but 

also were looking over a short time periods of 2 years for the Louisville study and 4 years for 

SNiPP. The WG downgraded PCV13-type disease mortality since the only evidence comes 

from ABCs, which captures inpatient mortality and in the outpatient setting, deaths that occur 

very proximally to the diagnosis of PCV13-type IPD only. Lastly, the WG downgraded the RCTs 

for SAEs because some of the trials had modified blinding procedures, relatively short follow-up 

periods, and some used a control group other than PPSV23. The WG noted that the 

observational studies had inadequate or no comparison group, but upgraded these studies for 

the SAE outcome since there have been multiple large observational studies with consistent 

results. Here is the GRADE Summary Table showing the final evidence types for benefits and 

harms:

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Outcome Design # studies 

[references]

Initial 

Evidence 

Type

Risk of 

Bias Inconsistency Indirectness Imprecision Evidence Type

Benefits

PCV13-type 

invasive 

pneumococcal 

disease (IPD)

RCT

1 — [1, 2] 1

Not 

serious N/A Serious Not serious 2

PCV13-type 

pneumonia 1 —[1, 2, 6] 1

Not 

serious N/A Not serious Not serious 1

Mortality from 

PCV13-type 

disease

1 — [1] 1

Not 

serious N/A Not serious Very serious 2

PCV13-type 

IPD

Observational

4 — [3-5] 3 Serious Not serious Serious Not serious 4

PCV13-type 

pneumonia

5 — [7, 9-

12] 3

Very 

serious Very serious Serious Very serious 4

Mortality from 

PCV13-type 

disease

1 — [5] 3 Serious N/A Serious Very 

serious 4

Harms

Serious 

adverse 

events

RCT 4 — [1, 13-

15] 1 Serious Not Serious Serious N/A 2

Observational 5 — [16-20] 3 Serious Not Serious Not Serious N/A 2

In summary, PCV13 is effective and efficacious in preventing PCV13-type IPD and efficacious in 

preventing NIPP, but the effectiveness against NIPP is inconsistent across studies. Since 2014, 

at the population level, no impact has been observed on IPD and data across studies for the 

impact on pneumonia are inconsistent. The remaining PCV13 disease burden is predominated 

by serotype 3. No impact has been demonstrated on mortality, and no concerning safety signals

have been detected.

To summarize the WG’s perspective on the benefits and harms of routine PCV13 use among 

older adults, PCV13 is effective in preventing disease amongst older adults, but the remaining 

disease burden is low and predominated by serotype 3. Based on this summary, the WG 

thought that the anticipated desirable effects would be small, but that the overall certainty of this 

evidence was judged to be low because of the limited and inconsistent results for pneumonia 

and mortality outcomes. For anticipated undesirable effects, no concerning safety signals have 

been seen since the 2014 recommendations were made with at least 40% coverage among 

adults 65 years and older. For these reasons, the WG’s perspective was that the anticipated 

undesirable effects are minimal with a high certainty in the level of the evidence. In terms of the 

balance of benefits and Harms of PCV13 use among older adults, the WG thought that the 

benefits of continued PCV13 use are relatively small, but outweigh the risks, which also are

small. Evaluating just the elements of the reviewed data to this point, the WG favored continuing 

routine PCV13 use for older adults.

Evaluating the values and preferences of the target population, there are very limited data for 

this element. In three patient-focused studies, participants perceived pneumonia as severe and 

sometimes fatal.1-3 However, there was a low perceived personal susceptibility of pneumonia.1-2

The WG’s perspective was that the potential protection against pneumonia likely outweighs the 

side effects of PCV13 for older adults [1 Doshi et al. 2016, 

2

 Brown et al. 2017 (PPSV23 only), 

3Kaljee et al. 2017].

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Assessing the available information in the EtR Framework, how older adults feel about the 

desirable effects balanced against the undesirable effects cannot be addressed with any 

certainty. However, the assessment by the WG was that there is possibly important uncertainty 

about how much adults ≥65 years old value the main outcomes. In summary, there is very little 

evidence on which to base a recommendation from this domain.

There are limited studies assessing acceptability among stakeholders as well, but the WG 

reviewed three studies directly addressing the policy question, which in summary raised the 

following themes. The current recommendations are confusing for providers.

1 However, 

providers when choosing to continue the recommendation or not, choose to continue with 

current recommendation.

2 Almost half of the immunization managers surveyed responded that 

keeping the current recommendations may be programmatically advantageous if new, higher 

valency conjugate vaccines were to be available soon.

3While there is insurance coverage for 

the current recommendations, reimbursement for vaccine is still a programmatic issue3[

1 Hurley 

et al. 2018; 2 Pfizer sponsored provider survey, unpublished, 2018; 3 Association of 

Immunization Managers (AIM) survey, unpublished, 2018].

The WG has deliberated on the domain of acceptability of continued PCV13 use amongst older 

adults, taking into account the following considerations. The considerations for discontinuing 

PCV13 are that the overall impact on PCV13-type disease from vaccinating older adults is 

minimal in the context of indirect effects from pediatric PCV use. Considerations for continuing 

PCV13 included that PCV13 can provide individual-level protection against the remaining 

burden of disease, and that frequent changes in recommendations may negatively impact the 

perceived importance of future adult vaccine recommendations and may present 

implementation challenges. With these different considerations, the WG’s opinions did not 

coalesce around a single judgment for this domain.

In terms of resource use, as was summarized by Dr. Leidner in his presentation earlier in the 

session, there is important uncertainty for some of the inputs, primarily regarding what the VE 

against pneumonia is for both PCV13 and PPSV23. However, the majority of base-cases and 

sensitivity analyses provide an estimate that is 2 to 12 times higher than what it was in 2013. 

This table compares resources used in 2013 compared to 2019:

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Comparing the results now with the evidence that went into the decision in 2014, in the first 

column are the 2013 model results. This was the estimated public health impact at the time of 

the decision. However, in 2014, it was anticipated that there may be additional indirect effects 

from pediatric PCV13 use, so the model was projected forward to 2019 when it was thought that 

the indirect effects would have reached their peak. Those model results are represented in the 

second column. The third and fourth columns are the current model estimates, first assuming no 

effectiveness against serotype 3 disease and then assuming 26% for ST3-type IPD and 45% for 

ST3 pneumonia. The assumptions have been updated with new information gained in the past 4 

years. Roughly, the cost in 2013 was $65,000 dollars per QALY. It was projected to be 

$287,000 dollars per QALY. And now that it is actually 2019, the cost is estimated to be

approximately $222,000 dollars per QALY assuming PCV13 effectiveness against serotype-3,

and $561,000 dollars per QALY assuming PCV13 is not effective against serotype 3. In terms of 

the WG’s perspective on the resources used, implicit in the economic models is the same level 

of uncertainty that exists in the evidence for the burden of disease and benefits from PCV13 use 

domains. However, with the updated information available now compared to 2014, the cost per 

QALY are estimated to be higher now than they were in 2013-2014 when the recommendation 

was made. The WG thought that PCV13 use among older adults was probably not a reasonable 

and efficient use of resources.

As the last domain in the EtR, the WG considered feasibility. The current recommendations are 

complex, but have been integrated into many health care and public health systems. Universal 

age-based recommendations are easier to implement than risk-based recommendations. 

Medicare currently covers the recommended pneumococcal vaccination series for adults ≥65 

years old. If a change in the current recommendations is made, CMS will review the new 

recommendation and the supporting evidence. It was brought up by WG members as well that 

some state regulations that allow public health nurses and pharmacists to provide PCV13 are 

tied to ACIP recommendations, and that effective communication strategies will be needed if 

policy changes are considered. In answering the final question regarding whether the current 

intervention is feasible to continue, the WG thought “probably yes.” PCV13 in series with 

PPSV23 is the current intervention, so continuing would mean continuing the status quo versus

removing PCV13 and returning to the previous recommendations of PPSV23 alone for adults 65 

years and older.

Now to bring everything together, the options for type of recommendations considered were the 

following:

A. We do not recommend the intervention (PCV13 in series with PPSV23 no longer 

recommended for immunocompetent adults ≥65 years old) 

B. We recommend the intervention for individuals based on clinical decision-making (PCV13 in 

series with PPSV23 would be given to immunocompetent adults ≥65 years based on 

patient-provider judgement)

C. We recommend the intervention (continue PCV13 in series with PPSV23 for 

immunocompetent adults ≥65 years old)

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As of the most recent discussions, most WG members were either in favor of discontinuing 

PCV13 (A) or recommending PCV13 for individuals based on clinical decision-making (B). A 

small minority of WG members supported continuing current recommendations (C). However, 

there were many key issues raised when considering these different recommendation options. 

Here is a summary of the key issues:

Reasons Raised in Favor of

Continuing Routine PCV13 Use

Reasons Raised in Favor of

Discontinuing Routine PCV13 Use

❑

❑

❑

❑

PCV13 is effective in preventing PCV13-

type pneumococcal disease.

PCV13-type disease has been reduced 

through indirect effects, but not 

eliminated.

It is easier to adhere to universal 

prevention strategies than to risk-based 

ones.

Frequent changes in recommendations

may negatively impact the perceived 

importance of future adult vaccine 

recommendations, and may present 

implementation challenges.

❑

❑

❑

❑

❑

The overall impact on PCV13-type 

disease from vaccinating older adults is 

minimal in the context of indirect effects 

from pediatric PCV use.

The low remaining burden of PCV13-type 

disease limits the potential benefit from 

direct effects.

There has been a lack of clear 

population-level impact on disease since 

2014.

This would be a more judicious use of 

resources.

Discontinuing PCV13 for older adults 

would be a simplification of the 

recommendations.

The next steps for the WG are to provide a brief summary of the EtR Framework to ACIP,

including any updates from studies being finalized, including the following: 

❑ The mathematical model estimating PCV13 direct and indirect effects against IPD

❑ The two case-control studies estimating PCV13 VE against IPD using ABCs IPD cases

❑ Trends by serotype from the Native American Adult Pneumonia Etiology Study, which was 

first presented in June 2018

❑ Results from a primary care provider survey focused on acceptability and feasibility

An ACIP vote is anticipated during the June 2019 meeting.

Discussion Points

Dr. Atmar observed that one of the issues he did not hear addressed regarded what resource 

utilization would result from removing the recommendation and then potentially re-initiating it 

within this population within a year or two when PCV15 or PCV20 become available. This is an 

important consideration, so any additional information that would inform ACIP’s deliberations 

would be beneficial.

Dr. Messonnier said that CDC agrees that this is a complicated topic and appreciates everyone 

thinking through what additional information may be helpful. CDC probably needs to pose that 

complex question to CMS, which they will do in order to try to acquire some information for 

ACIP for June. She invited everyone to identify other information that would be helpful.

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Dr. Foster (APhA) suggested that pharmacists could weigh in on the acceptability issues for 

which the WG could not make a decision. Probably 100% of states permit pharmacists to 

administer this vaccine, so pharmacy is very much involved in this process. APhA puts a lot of 

resources into getting the recommendation understood within pharmacies throughout the 

country. He recalled some meningococcal discussions pertaining to ACWY135 being kept in the 

schedule twice because of programmatic issues, so he thought this was a feasible thing to do. 

He thought that removing the recommendation now and then trying to implement something 

within one to two years if new vaccines do become available would be very difficult to do with 

the pharmacy setting. He also thought that in 2014 when the decision was made to revisit this in 

2018, it was probably anticipated that there would be more data available. From the standpoint 

of pharmacy, he was supportive of continuing with the current recommendation until such time 

as additional vaccines are available.

Dr. Ault asked whether there are all-cause mortality data from the large Medicare and Medicaid 

dataset that was just presented.

Dr. Matanock indicated that they have some of that information and can provide it within the 

summary during the June 2019 meeting. They have assessed the CFR, but she was not sure 

whether mortality over time had been examined.

Dr. Ezeanolue said this reminded him of the decision ACIP had to make several meetings ago 

about LAIV in that there were the facts before them, as well as the programmatic issues that 

had to be considered. The majority of key issues Dr. Matanock reviewed for continuing versus 

discontinuing are programmatic. It is known from the data that there has not been any 

population-based impact, but there will be some important programmatic issues if it is removed. 

The question arises regarding what factors ACIP should consider in making its decision. The 

facts are before them that there has been no population-based impact. He requested further 

insight from CDC about how to weigh these two aspects in terms of whether the anticipated 

programmatic issues were enough to continue this vaccine. 

Dr. Messonnier replied that programmatic issues are important enough. Dr. Wharton always 

reminds her when complicated issues such as this arise that this is why CDC has ACIP. She 

completely agrees that this is an incredibly complex issue that is at the boundary of data and 

judgment. Over the past couple of years and many of the issues that CDC poses to ACIP are in 

this same space in which it is not so obvious what to do. She thought Dr. Lee could comment on 

why this has been so difficult within the WG.

Dr. Lee commented that the reasons the “acceptability” box is so broad is because the entire 

WG as a whole has swayed from one side to the other, as have individuals on the WG. The 

problem is that they agree with all of the statements. There is nothing wrong with any of the 

arguments, so she thinks this is a judgment call they are going to be forced to make.

Dr. Stephens pointed out that this platform was introduced in 2014 and he did not think the 

impact of that has been realized. The order in which these vaccines are administered is 

important in that it really is a prime/boost strategy with a conjugate followed by a 

polysaccharide. To go back to a polysaccharide alone strategy seems to him to be a mistake 

based on his reading of the data. He did not think they had seen enough data with the proper 

use of the conjugate followed by the polysaccharide. He also would argue with the term 

“immunocompetent.” These are not immunocompetent individuals in the sense that many of 

them have conditions or significant conditions with medications and so forth. This is not 

“immunocompetent” as it would typically be defined. He urged them to think further about this 

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issue. More data in terms of this platform is important, and he agrees about the coming 

introduction of potentially even better conjugate vaccines for this population.

Dr. Baker (IDSA) agreed with Dr. Stephens’ statements.

Dr. Talbot asked if there is a population of Native Americans who are still at high risk for 

pneumococcal disease because they have not eliminated disease in children, whether that 

would require another WG and vote to include an indication just for them.

Dr. Cohn indicated that procedurally from an ACIP perspective, that group would have to be 

considered and voted upon separately as a high risk group. If the recommendation was taken 

away entirely, another WG would be needed. If individual clinical decision-making is kept, there 

potentially could be some broad-based decisions by IHS.

Dr. Weiser (IHS) emphasized that IHS is not the only group that provides immunizations for 

AI/AN. For example, the recommendations pertaining to influenza and treating influenza with 

antivirals has made a major impact on helping others who are not part of the IHS system to do 

the right thing. He would like to hear more about the Native American Adult Pneumonia Etiology 

Study during the next meeting.

Dr. Matanock indicated that the Native American Adult Pneumonia Etiology Study was

presented initially in June 2018. At that time, Dr. Hammett presented information about what 

was known at that point amongst Navajo and Apache for etiology of pneumonia and the impact 

of PCVs overall in Alaska Natives and American Indians living in the Southwest. While there 

have been similar impacts, the rates of disease are still higher. The etiology study is not pre2014, so it is not possible to look at impact from this. Dr. Hammett is going to try to estimate VE, 

but this is likely to be difficult given the very high coverage rates in that population.

Dr. Walter said he was still struggling with the first presentation in terms of the direct effects of 

PCV13 when ST3 is removed. The summary presentation accounted for all serotypes, and he 

wondered if that was the correct way to look at this. That is, ST3 was not removed in the last 

presentation but perhaps should be.

Dr. Pilishvili clarified that the study utilizes surveillance and coverage data in order to tease 

apart direct and indirect effects. They are using essentially what is observed and trying to 

attribute how much of it was due to direct versus indirect effects. When ST3 is removed, the 

trend looks very different. Therefore, more is to be attributed to direct effects given the 

coverage. When ST3 is included, the trend is flat and there is nothing to attribute to direct effect. 

This is not a direct effectiveness study which compares vaccinated to unvaccinated. She 

thought they should separate direct effectiveness where effectiveness was moderate to low 

when vaccinated are compared to unvaccinated and the impact over time.

Dr. Cohn added that further consideration can be given to whether ST3 should be removed, 

which can be presented during the next meeting.

Dr. Goldman (ACP) agreed that this is a complex issue and as a private practitioner, he always 

struggles with population health versus the individual patient in front of him. He always has been 

taught, trained, and still believes that his most important responsibility at that moment the 

patient is in front of him at that time until the next patient comes in and becomes the most 

important patient. While population health is of great importance to ACIP, he thinks they also 

must remember that even if they are reducing pneumonia risk in one patient as practicing 

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physicians, that is of great concern. There needs to be leeway for individual clinical decisionmaking. While cost and health coverage are important, they must stress the fact the vaccine 

does have some benefits. It is not zero. It is not completely ineffective. Even if they are reducing 

the risk of a pneumonia-related death for one patient, it is 100% for that one patient.

Dr. Frey said it would help her think about the overall picture if they could find out where PCV10 

and PCV15 are in their development and the timeline for potential applications/approvals.

Dr. Messonnier suggested that this be added to the list of items ACIP would like to hear about 

during the next meeting. They know what the companies will say and can include it, but as they 

all know and FDA will confirm, those timelines are always incomplete.

Dr. Grogg (AOA) emphasized that they finally got their physicians trained to give the Prevnar 

13® Prevnar at 65 years of age and PNEUMOVAX® 23 at 66 years of age. There are questions 

about effectiveness and new vaccines are coming out, so his suggestion was to keep the 

recommendation as is until more is known.

Dr. Ezeanolue asked whether ACIP has to take a vote in June, or if it would be possible to defer 

that vote and allow the WG to continue in order to determine whether there will be an increase 

in uptake in that 20% uptake may be insufficient for them to judge whether there is going to be a 

population-based impact. It seems the infrastructure that already is built could wait until 

information on this and new products becomes available.

Dr. Cohn replied that ACIP does not have to vote on this issue. Not voting on this issue is 

essentially maintaining the current recommendation, so it is still a decision. In terms of 

implications and future data, ACIP has so many issues coming down the pipeline in the next 

couple of years, closing out this issue for a period of time would be helpful. 

Dr. Ezeanolue emphasized that the problem is that they are not really closing it out. If they make 

a decision now and have to come back in a year or so, it will seem like they are not sure what 

they are doing.

Dr. Cohn indicated that they could discuss the WGs terms of reference and how they prioritize 

after there is more feedback on this particular decision. The answer is that they do not have to 

vote on this decision. That is up to ACIP.

Dr. Moore said she was one of three minds about this depending on the moment. It might help 

her to know what the potential inadvertent unintended consequences might be to particularly 

vulnerable populations if the recommendation was changed. Risk-based recommendations are 

difficult to implement and age-based recommendations are much easier to implement. This has 

been an age-based recommendation for a while. Perhaps it would be beneficial to hear about 

any data on subpopulations or vulnerable communities like AI/AN who might have special 

circumstances that ACIP has not discussed.

Dr. Coyle (AIRA) pointed out that from a systems perspective, it is very helpful for ACIP to 

consider what they want the provider to do, what information they want them alerted to, and how 

that reacts different. For example, if a provider is looking at the recommendation, does ACIP 

want that displayed ahead of time and recommended for all patients or a certain percent of that, 

or is it that the patient needs to know about the recommendation before they walk in the door? 

From a systems perspective, it would be helpful for ACIP to consider this as they evaluate their 

decisions.

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Dr. Bernstein expressed interest in knowing the annual NNV and cost per QALY for other 

vaccine-preventable diseases in comparison to this.

Dr. Cohn responded that this is not typically presented, as they think that these are each 

individual decisions and there is wide variation. Some background information can be provided 

for ACIP. She invited Dr. Baker to clarify whether her agreement with Dr. Stephens’ statements 

was a personal opinion or an IDSA perspective that has been discussed.

Dr. Baker (IDSA) clarified that it was her personal opinion, but they are interacting officially with 

the IDSA, especially if there will be a vote because this is a very important issue. However, IPD 

is a very uncommon event due to the vaccine serotypes. There is a huge indirect effect due to 

pediatric and adult vaccine providers. It is very difficult to measure direct effects. For example, 

how many people 65 years of age and older who got PCV13 did not get IPD? How many people 

had mild CAP, went to the doctor, and got medication? It is difficult to be precise. Either she or 

Dr. Duchin will comment on the IDSA perspective during the June meeting. She suspects that 

for the people who are vaccinating within the IDSA, which includes pediatricians and adult 

providers, the issues pertaining to dismantling and re-mantling systems and future advance 

conjugate vaccines are all going to be very important. Immunizers are physicians and their duty 

is to deal with individual patients, and it is difficult.

Dr. Messonnier indicated that given the complexity of this situation, it would be very helpful for 

the liaisons to take this back to their organizations and be prepared in June to provide input. If 

organizations, especially those that are major stakeholders in this issue, want to take a position 

on this, it would be very helpful for the voting members to hear that feedback.

Dr. Atmar pointed out that one of the issues with influenza vaccine after the Medicare 

Demonstration Project and the increased uptake of influenza vaccine in the elderly population, 

was that there was great concern about being able to demonstrate population-based effects. 

They eventually moved to the test-negative design to show VE in various age groups. In fact, 

that may be similar here and perhaps they should seek input from the modelers on this. The 

lack of population-based effects may be somewhat troublesome, but he did not think it should 

be fatal. Some of the data showing evidence of continued direct effects should be given some 

import.

Dr. Szilagyi said that like everyone, he was really struggling with this. In terms of the 3 possible 

decisions, he thought it might be helpful for the WG to think through what guidance ACIP would 

be able to provide if there was individual-decision recommendation. As a primary care physician 

who administers vaccines, albeit it to children, he was having a hard time ascertaining what kind 

of logical guidance would help a primary care internist or family physician. This aligns with Dr. 

Stephens’ comment that a 65 year old is not the same as a 75 year old. It is difficult to judge 

immunocompetence because there is an enormous range, and he personally would have a hard 

time trying to determine a patient’s risk.

With some institutional memory having been on the committee for 5 years, Dr. Romero recalled 

a vote on meningococcal B vaccine and the discussion Dr. Frieden had with ACIP. To 

paraphrase that discussion, Dr. Frieden said that they should not be paralyzed by lack of data 

but should react on the data that they have, and project their decisions based on the facts 

present. They should make reasonable assumptions and if those assumptions need to be 

modified at a later date, so be it. They are tasked to come up with a plan or reasonable process 

forward, which is important for the committee to bear in mind.

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Introduction

David S. Stephens, MD 

Chair, Meningococcal WG 

Advisory Committee on Immunization Practices 

Emory University 

Dr. Stephens introduced the Meningococcal Vaccine WG session. Two serogroup B 

meningococcal (MenB) vaccines were licensed for persons aged 10 through 25 years in 2014 

and 2015. The first is MenB-FHbp (Trumenba®, Pfizer), which is indicated for persons at 

increased risk for MenB disease. Trumenba®is administered as a 3-dose series at 0, 1-2, and 6 

months. Healthy adolescents are recommended to receive a 2-dose series administered at 0 

and 6 months. The second is MenB-4C (Bexsero®, GlaxoSmithKline), which is a 2-dose series 

administered at 0 and ≥1 month.

In February 2015, ACIP recommended that the following persons aged ≥10 years at increased 

risk for MenB disease receive a MenB primary series:

❑

❑

❑

❑

Persons with complement component deficiency, including complement inhibitor use

Persons with functional or anatomic asplenia

Microbiologists routinely exposed to isolates of Neisseria meningitidis (N. meningitidis)

Persons exposed during an outbreak

These groups are also recommended to receive a quadrivalent meningococcal conjugate, 

MenACWY, as a primary dose or series. A booster dose is recommended every 5 years 

thereafter for as long as increased risk remains.

In June 2015, ACIP also recommended that adolescents aged 16 through 23 years may be 

vaccinated with a MenB primary series based on individual clinical decision-making, with a 

preferred age of 16 through 18 years.

The question before the committee during this session pertained to MenB booster doses. ACIP 

does not currently recommend MenB booster doses for persons at increased risk for MenB

disease. This recommendation would be off-label as booster vaccination currently is not 

licensed. Data and considerations for MenB booster doses were presented during the February

2017 ACIP meeting. ACIP requested further data to inform policy options. Additional data on 

immune persistence following a MenB primary series and immunogenicity, safety, and 

persistence of a MenB booster dose have been generated. However, the manufacturers have 

indicated that no further data are forthcoming.

In terms of activities, the WG has: 1) reviewed data on persistence of the immune response 

following a MenB primary series and immunogenicity, persistence, and safety of a MenB 

booster dose; 2) formulated policy questions and evaluated the quality of evidence for MenB 

booster doses; and summarized WG perspectives and developed potential MenB booster policy 

options for ACIP feedback.

Meningococcal Vaccines

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The agenda for this session included presentations on the following topics:

❑

❑

❑

❑

A summary of the data on the immune persistence following a MenB-FHbp primary series 

and immunogenicity and safety of a MenB-FHbp booster dose

A summary of data on the immune persistence following a MenB-4C primary series and 

immunogenicity and safety of a MenB-4C booster dose

GRADE and EtR Framework for MenB booster doses

WG interpretation of the data, considerations, and next steps

Safety and immunogenicity of a booster dose of Trumenba®(MenB-FHbp)

Paul Balmer, PhD 

Medical Development, Scientific, and Clinical Affairs 

Pfizer Vaccines

Dr. Balmer presented data generated on the safety and immunogenicity for a MenB-FHbp 

booster dose. As a reminder, MenB-FHbp is licensed for individuals 10 through 25 years of age 

for the prevention of serogroup B meningococcal disease. There are two dosing schedules: 1) 

For individuals at increased risk for meningococcal disease and for use during MenB disease 

outbreaks, ACIP recommends that 3 doses of Trumenba® be administered at 0, 1–2, and 6 

months; and 2) When given to healthy adolescents who are not at increased risk for 

meningococcal disease, ACIP recommends that 2 doses of Trumenba® should be administered 

at 0 and 6 months.

As a reminder, Pfizer’s MenB vaccine is based on a surface-exposed factor H binding protein 

(FHbp). Pfizer looked at an extensive collection of isolates from North America and Europe and 

found that FHbp is expressed in >95% of invasive MenB strains. Importantly, FHbp segregated

into two distinct subfamilies, A and B. If a vaccine targets FHbp, it is very important to address 

this by including one protein variant from each subfamily. To do that, Pfizer included variants 

A05 and B01. Breadth of coverage is important for protein-based MenB vaccines. It is important 

to be able to deal with diverse MenB strains, but it is not possible to test against every possible 

MenB strain. The approach Pfizer took was to use the human serum bactericidal assay (hSBA), 

which is an established correlate to predict protection. Four MenB strains were selected that 

were the most prevalent in the US in terms of their clonal complex, including A22, A56, B24, 

and B44. Importantly, these variants are not matched to the vaccine components. This allows 

for true breadth of coverage [Madico et al. 2006; Schneider et al. 2006; Mascioni et al. 2009; 

Seib et al. 2009; Ala’Aldeen et al. 2010; McNeil et al. 2009; Jacobson, Moellig, Olcen 2009, 

McNeil et al. 2018].

In terms of study designs, these studies take a long period of time. Of the 3 parent studies, 

Studies 1010 and 1015 were 3-dose schedules. Study 1012 had groups who received either a 

2-dose or 3-dose schedule. These subjects were then rolled over into Pfizer’s Phase 3 

Extension Study, 1033, in which persistence was evaluated for 48 months. A booster dose was 

then given to subjects who originated from Study 1012 and 1010 at 48 months and followed 

persistence out to 12 months and then 26 months.

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Regarding safety, what was observed was that a booster dose had a very similar safety profile 

compared to the primary series. Pain at the injection site was the most commonly reported local 

reaction, reported by 84.4% to 93.5% of subjects. Fatigue (51.9% to 65.6%) and headache 

(37.5% to 56.3%) were the most commonly reported systemic events. Of the subjects, 3.7% to 

12.5% reported ≥1 AE. Among the subjects, 3 reported related AEs. One of those was an ILI 

that was classified as an SAE. This was among a group from Study 1012 who received a 2-

dose schedule at 0, 2 months who did not roll through the entire persistence and postpersistence. There were no reported AESs during the persistence phase post-booster up to 26 

months.

Dr. Balmer split the immunogenicity data into two sections in order to assess the 2-dose and 3-

schedules separately. For the 2-dose schedule, looking at the proportion of subjects with a titer 

≥1:4, at 1 month post-last dose, a significant proportion of individuals had an hSBA titer of ≥1:4. 

A decline was observed at 12, with a plateau at 48 months. Overlaying the booster data, a nice 

booster response was observed in terms of the proportion of individuals above this threshold 1 

month after the booster dose. Looking at the data from 12 months and 26 months post-booster, 

persistence appears to have been improved. Those were the data for the four individual strains.

Looking at the data in terms of the proportion of individuals who were able to make a response 

at this threshold against all 4 strains, which Pfizer thinks of as evaluating the breadth of 

coverage the vaccine is able to give, the pre-vaccination data show that without vaccination, 

individuals found it difficult to mount an hSBA protective level across diverse strains. At 1 month 

after the 2-dose schedule, 73% of individuals were able to respond to all 4 strains. This declined 

at 12 months and plateaued out to 48 months. With the booster given at 48 months at the time 

of the plateau when immunity was at 23.8%, by 1 month post-booster the protective level across 

diverse strains was better at approximately 92%, at 12 months 62.7%, and at 26 months 42.1%.

From the parent studies, Study 1015 had a control group. This allowed for a comparison 

between the two groups vaccinated with MenB-FHbp and a control group at 1 month post-dose 

last dose (in this case 0, 2, 6 months) against the baseline at each time point. Similar to the 2-

dose regimen, that declines after the nice response 1 month after the final dose. There is 

separation between the two groups until 48 months.

Looking at the individual 4 strains for the 3-dose schedule, the profile is exactly the same as the 

data for the 2-dose schedule with better persistence at 12 and 26 months. Looking at the 

response against all 4 strains, the profile is very similar at 1 month when approximately 84% of 

individuals are able to mount a response against all 4 strains. The persistence profile looks 

exactly the same. Looking at the booster dose data, there is a nice booster response with up to 

100% of individuals responding to all 4 strains at 1 month. The persistence of individuals above 

this threshold remains higher post-booster.

The profiles for the 2-dose and 3-dose schedules are very similar in terms of their profiles. In 

terms of persistence post-primary series, no difference was observed irrespective of schedule. 

The parent study actually had groups with a shorter interval between the 2 doses as well. In 

terms of persistence post-primary series, a range was observed for the 4 strains. This is 

important because it provides an indication of the range that will be seen against strains which 

are diverse and not matching the antigen, and a feel for what persistence will be against diverse 

circulating strains. The profile looks very different after the booster, with a convergence of the 

range across the 4 strains. This indicates that there is maturation of the bactericidal response, 

and there probably is going to be a better persistence of breadth of coverage.

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For high risk groups, these data suggest that a 3-dose series followed by a booster dose will 

enhance persistence of breadth of coverage. For individuals at increased risk due to an 

outbreak, the data suggest that a single dose of MenB-FHbp can be given to those previously 

vaccinated with a primary series of MenB-FHbp regardless of whether it was a 2-dose or 3-dose 

schedule. These data on persistence of protective responses against diverse strains expressing

non-matched FHbp variants post-booster dose provide further insights on the optimal way to 

use these protein-based vaccines to prevent MenB disease across adolescents within the 

population.

Discussion Points

Dr. Atmar asked whether Dr. Balmer could reassure them that the data for the persistence of 

antibody in the larger group, for the subgroup that had the booster, was similar or representative 

of what was seen if only the group who was boosted was analyzed. That is, somehow the 

booster group did not have baseline and persistent antibody to a greater degree than the larger 

group of whom did not get boosted.

Dr. Balmer indicated that in Study 1015, they received the 3-dose schedule and did not receive 

the booster dose. The data between that group plus the subgroup that ran through to booster 

were pretty similar.

Update on BEXSERO® (MenB-4C) Regarding the Need for and 

Timing of MenB Booster Doses in Individuals at Increased Risk 

Phil Watson, PhD

US Medical Affairs Lead

Meningococcal Vaccines 

GlaxoSmithKline (GSK)

Dr. Watson indicated that GSK’s intention was to help provide information that could inform the 

booster recommendations for MenB vaccines. This presentation was created at the request of 

the ACIP Meningococcal WG and included a recap on the vaccine attributes and data pertinent 

to this particular policy question.

As a reminder, BEXSERO® comprises 4 major antigenic components: factor H binding protein 

(fHbp), Neisseria heparin-binding antigen (NHBA), (Neisserial adhesin A (NadA), and Porin A 

(NZ PorA P1.4). Each has a distinct target and antibodies to each component are independently 

bactericidal, but also can work in synergy. In the US, BEXSERO® has been licensed for persons 

aged 10 through 25 years of age since 2015 as a 2-dose series. It is licensed elsewhere in the 

world from 2 months of age, and several countries have implemented regional or national 

immunization programs.

BEXSERO® has been used extensively worldwide since licensure, with over 30 million doses 

distributed to date. Vaccination programs have been implemented in a range of settings, 

including populations with infants, children, adolescents, and university students. The largest 

program to date involved routine vaccination of all UK infants. In the 3 years since 

implementation, disease incidence has been significantly reduced in the vaccine-eligible cohort. 

The provisional estimate of VE is approximately 70%. UK authorities have also reported no 

significant safety concerns after the use of more than 3 million doses. A large regional campaign 

in Canada evaluated over 2 years after vaccination showed that disease risk was significantly 

reduced by vaccine use in a population ranging in age from 2 months to 20 years of age. These 

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findings along with observations from Australia, the US, and elsewhere confirm that BEXSERO®

provides direct protection and has an acceptable safety profile.

The data relating to the specific policy decision at hand come from 4 clinical trials in which 

BEXSERO®immune responses were evaluated in adolescents and young adults. These studies 

were undertaken in several countries (UK, US/Poland, Canada/Australia, and Chile), with followup periods ranging from 11 months to 7.5 years.

In terms of immune responses at 1 month after the primary series completion in each of these 

studies, robust responses to the 2-dose primary series were evident across the board with 

between 68% to 100% of subjects having protective titers against the individual vaccine 

components. The safety findings were consistent across all studies. Most events were mild or 

moderate and resolved by Day 7. There was no evidence of increasing severity after a second 

or subsequent dose.

Regarding immune responses at different timepoints after primary series completion, the followup interval increased from 11 months in the UK to 7.5 years in Chile. In the UK where 

responses were measured 11 months after vaccination, 85% to 97% of subjects retained 

protective levels of antibodies to the individual vaccine components. An additional analysis of 

the same data included in the FDA approved label in the US showed that serum from 66% of 

these individuals was actually bactericidal against all 3 of the indicator strains.

In the studies with longer follow-up periods, Canada/Australia and Chile, it is evident that 

antibodies may persist at protective levels for several years after primary series completion. 

After 4 years, between 9% and 84% of subjects maintained protective titers to the individual 

vaccine components. After 7.5 years, 29% to 84% of subjects maintained protective titers to the 

individual vaccine components. In every study, antibodies induced by each component waned 

at different rates. At the longer time points, fewer subjects retained protective titers for PorA, 

suggesting that antibodies to this component may wane relatively quickly. This was as expected 

and is consistent with observations with studies of other vaccines.

Importantly, the clinical impact may be limited as <1% of US MenB strains are covered only by 

this vaccine component. It also is worth noting that across all 4 studies, immune persistence 

data were available from only 18 US subjects. Caution should, therefore, be exercised in 

attributing more or less weight to any one of these individual studies when trying to generalize 

for the wider US population.

Moving on to booster responses, there are data from 2 studies in which a single dose of 

BEXSERO® was given after 4 or 7.5 years after primary series completion. For all 4 

components, robust responses were evident to a booster given either 4 or 7.5 years after 

priming. The mean antibody titers after the booster doses were higher than the titers achieved 1 

month after the 2-dose primary series. The kinetics of the booster dose also have been 

assessed by measuring GMTs up to 3, 7, and 30 days. In both studies, strong responses to all 

vaccine components were evident by Day 7. The reactogenicity of a booster dose has been 

evaluated in both studies as well. There was no evidence of increased reactogenicity after a 

booster dose compared with the primary vaccination, and AE rates were similar in the follow-on 

subjects and vaccine-naïve groups.

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The persistence of antibodies after a BEXSERO® booster have not been studied in clinical trials. 

Limited data are available from a study in which individuals were primed with BEXSERO®, 

followed for up to 2 years, and then boosted with an investigational MenABCWY vaccine, which 

contained all of the components of the BEXSERO® and those of a quadrivalent MenACWY 

vaccine. Of subjects, 45% to 100% of subjects had protective titers 1 year after MenABCWY. 

The extent to which these responses accurately reflect antibody persistence after a BEXSERO®

booster dose is unknown, but they were included for completeness and consideration.

When trying to predict the longevity of disease protection after BEXSERO® vaccination, the 

respective contribution of each vaccine component must be considered. As a reminder, 

circulating MenB strains are highly diverse and the prevalence and expression level of each 

antigen varies among strains. In the US, it is predicted that 91% of circulating strains are 

covered by BEXSERO® and more than 47% of these strains are covered by two or more 

vaccine components. NHBA and fHbp are the two vaccine components that contribute the most 

to strain coverage (83% and 53%, respectively). Since the prevalence of each antigen is known 

among circulating strains and the rates at which antibodies to each component wane, it is 

possible to integrate these two datasets and use modeling to predict overall disease protection 

over time.

The results of this modeling come from the immunogenicity data from the US/Poland and 

Canada/Australia studies. Whichever immunogenicity data are used, overall protection is 

predicted to last several years after primary vaccination. This sustained effect can largely be 

attributed to the relatively slow waning of fHbp and NHBA antibodies, the vaccine components 

that contribute the most strain coverage. The more rapidly waning of PorA antibodies mentioned 

previously has relatively little impact on protection over time, because less than 1% of strains 

rely solely on this antigen for vaccine coverage.

Modeling also has been used to predict the duration of protection after a BEXSERO® booster 

dose. As one might expect, responses are predicted to be sustained for longer after a booster 

dose than after priming. It also is worth noting that these predictions of protection may be 

conservative because the underlying assays, hSBA and MATS, do not capture the synergistic 

effects between antibodies to each antigenic component.

Before summarizing, Dr. Watson reminded everyone that the immunogenicity and safety of 

BEXSERO® has been studied in individuals with increased risk due to underlying medical 

conditions. These data were presented previously by CDC in 2017. Response in children with 

asplenia or splenic dysfunction were similar to responses in healthy children. However, there 

was a trend toward reduced immune responses in children with complement deficiencies and 

those on eculizumab therapy.

To summarize the data, experience from large vaccine programs demonstrates the impact, field 

effectiveness, and tolerability of BEXSERO®in populations of all ages. Vaccine-induced 

antibodies persist to varying degrees for up to 7.5 years after a 2-dose primary series. The 

integration of immunogenicity and strain coverage data suggests the protective benefits of a 2-

dose series may be sustained for several years. A single booster dose administered up to 7.5 

years after priming elicits robust responses by Day 7. Higher titers have been observed after the 

booster dose than after priming, which is predictive of a more sustained response.

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In terms of MenB vaccination policy considerations, it remains the case that sporadic exposure 

actually accounts for the majority of MenB cases in the US—not outbreaks. In an outbreak 

where risk is substantially elevated, the priority is to quickly achieve high titers in the population 

at risk. In these circumstances, previously vaccinated individuals may already be protected from 

their primary series. In addition, these individuals can be boosted quickly within 7 days of a 

single dose. By contrast, vaccine-naïve individuals will need 2 or 3 doses over a period of 1 to 6 

months, depending on the vaccine. Recent publications have shown that series completion in 

this setting can be challenging and problematic. Taken together, these considerations highlight 

the value of MenB vaccination at age 16 to 18 years to help provide protection during the period 

of increased age-based risk.

Discussion Points

Dr. Quash (NACI) requested clarification regarding what the primary series schedule was.

Dr. Watson indicated that in all of the studies he described, the schedule was 0,1 months with 

the exception of the small study, which had the MenABCWY follow-up where the initial series 

was 0,2 months. 

EtR and GRADE: MenB Vaccine Booster Doses for 

Persons at Increased Risk for Serogroup MenB Disease

Catherine Bozio, PhD, MPH 

Epidemiologist, Division of Bacterial Diseases 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Bozio presented on the EtR Framework, including the grading of recommendations, 

assessment, development, and evaluation (GRADE) for MenB vaccine booster doses for 

persons at increased risk for MenB disease. She first presented some background on 

meningococcal disease and the WG’s over-arching policy question, and then delved into the 

EtR criteria, including GRADE, during which she presented evidence for each criterion and 

provided the WG’s interpretation.

Meningococcal disease is a rare but severe infection that can progress rapidly. Among persons 

with meningococcal disease, 1 in 10 die despite proper antibiotic treatment and 1 in 5 survivors 

have long-term sequelae. The incidence of meningococcal disease has been low, and rates are 

declining. A decline also has been seen in serogroup B disease, which accounted for 

approximately 40% of cases in 2017.

ACIP recommends that persons at increased risk for MenB disease receive a MenB primary 

series. Available evidence suggests that antibodies wane in the years following completion of 

the primary series, and MenB booster doses may be necessary to sustain protection. However, 

the goals of a booster dose differ by the reason for the increased risk. Persons with underlying 

conditions or microbiologists need protection for as long as the increased risk remains; 

whereas, among persons at-risk during an outbreak, rapid, short-term protection is prioritized.

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The WG’s over-arching policy question was, “Should persons vaccinated with a MenB primary 

series who remain at increased risk for MenB disease receive a MenB booster dose?” The 

population was persons who were at increased risk due to specific underlying conditions and 

microbiologists, and persons during a MenB disease outbreak. The intervention was either a 

MenB-FHbp or MenB-4C booster dose, and the comparison was no MenB-FHbp or MenB-4C 

booster dose. The outcomes of interest related to the MenB booster dose were vaccine 

effectiveness, immunogenicity, persistence of the immune response, immune interference due 

to co-administration with other vaccines, and SAEs. For GRADE, there were four PICOs, two for 

each group at increased risk and two for each MenB vaccine.

For the evidence retrieval, a systematic review was conducted of studies in any language from

PubMed, Medline, Embase, CINAHL, Cochrane, Scopus, and clinicalstrials.gov databases 

using the search string: “booster” AND [“serogroup B meningococcal vaccine” OR “recombinant 

meningococcal B vaccine” OR “MenB vaccine” OR “Bexsero” OR “MenB-4C” OR “rMenB±OMV 

NZ” OR “4CMenB” OR “Trumenba” OR “rLP2086” OR “Factor H binding protein vaccine” OR 

“FHbp”]. Efforts were made to obtain unpublished data. Studies were included that presented 

primary data on MenB booster doses in subjects who received a licensed MenB primary series 

at at least 10 years of age. An investigational combined serogroup vaccine, MenABCWY,

booster dose was included as a proxy for MenB booster dose if the MenB vaccine component 

was identical to the licensed MenB formulation. One study with unpublished data was identified 

based on presentations to the WG. Additionally, 131 references were identified in the database 

search. After screening the title, abstract, and article, 4 studies were included in the GRADE 

analysis.

Short-term immunogenicity of the booster dose, persistence of the immune response to the 

booster dose, and SAEs from the booster dose were included in the evidence profiles. Given 

the differences in the populations and the goals of the booster dose, EtR was completed 

separately for each population at increased risk. The data reviewed as part of the GRADE 

analysis were included as supplementary slides, and the evidence included in the profiles is the 

same for both populations at increased risk. 

Dr. Bozio presented EtR for persons with underlying conditions and microbiologists, starting with 

stating the problem. The burden of serogroup B meningococcal disease among persons at 

increased risk is not well-known due to limitations in national surveillance. The magnitude of 

increased risk in these persons can be up to 10,000-fold. Based on the population estimates for 

each group, these persons comprise less than 0.1% of the US population aged at least 10 

years.

Regarding benefits of the MenB booster dose, no data are available on its effectiveness or 

duration of protection in persons with underlying conditions. Additionally, immunogenicity and 

antibody persistence to the MenB vaccine may differ in persons with underlying conditions. In a 

GSK study examining the MenB-4C primary series, the immunogenicity in children and 

adolescents with asplenia was similar to that in healthy persons, but was lower in persons with 

complement deficiencies. Further, meningococcal vaccination may confer little to no protection 

in persons taking eculizumab. Regarding potential harms, evaluations including more than 

69,000 healthy adolescents and adults have demonstrated the safety of both MenB-FHbp and 

MenB-4C primary series. The undesirable effects of repeated MenB booster doses or in 

persons with underlying conditions have not been assessed.

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For GRADE, the WG evaluated data on the MenB-FHbp booster from one unpublished study 

by Pfizer. This observational study was an extension study that included participants who were 

previously enrolled in an RCT on the MenB primary series in four European countries. Healthy 

persons received the MenB-FHbp booster dose 48 months after the 2- or 3-dose MenB primary 

series. No data on a comparison group were available. Short-term immunogenicity, persistence 

of the immune response, and SAEs were outcomes of interest. As a reminder, the data 

reviewed for the GRADE analysis were included as supplementary slides.

For the MenB-FHbp booster dose, the WG evaluated evidence for short-term immunogenicity, 

persistence of the immune response, and SAEs from one observational study, though not all 

criteria were applicable. For all outcomes, the WG had serious concern for risk of bias, 

specifically selection bias. All of the subjects enrolled in the extension study related to the 

booster dose accounted for 14% of those who participated in the parent study. The WG 

downgraded for indirectness because data were available for healthy persons, but not for 

persons with certain underlying conditions. The WG also downgraded for imprecision because 

the small number of subjects resulted in wide confidence intervals regarding persistence of the 

immune response and may not be able to detect rare SAEs. The evidence type across these 

outcomes was a 4, indicating studies with important limitations, and the overall certainty of 

evidence was very low.

Moving onto the MenB-4C booster, data were available from three studies. The two 

observational studies from Nolan 2019 were both extension studies that included participants 

who were previously enrolled in RCTs on the MenB primary series in Australia, Canada, and 

Chile. Healthy persons received the MenB-4C booster dose 4 or 7.5 years following the 2-dose 

MenB primary series. For both studies, the comparison group was MenB vaccine-naïve subjects 

who received 1 MenB-4C dose. Short-term immunogenicity results were presented for each 

study, and data on serious adverse events from these studies were combined and analyzed as 

one study, as per the vaccine manufacturer. 

The study from Szenborn 2018 was an RCT in the US and Poland and also was an extension 

study. Healthy subjects were randomized to receive a booster dose based on the primary series 

they received. The intervention was the MenABCWY booster dose, with MenB component 

identical to that of licensed product, 2 years after the primary series. The comparison group 

included subjects who were received the MenACWY vaccine as the primary series, but were 

MenB vaccine-naïve, and one MenABCWY dose. The outcomes of interest were short-term 

immunogenicity, persistence of the immune response, and SAEs.

For the MenB-4C booster dose, the WG evaluated evidence for short-term immunogenicity from 

two observational studies. The WG had serious concern for risk of bias, specifically selection 

bias. All of the subjects enrolled in these extension studies accounted for 41% of those who 

participated in the parent studies. In the Australia and Canada extension study, the racial 

distribution differed among those who enrolled versus those who did not enroll. The WG had no 

serious concerns with inconsistency, but downgraded for indirectness because data were 

available for healthy persons, but not for persons with certain underlying conditions. The WG 

had no serious concerns with imprecision, and there were no other considerations.

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Evidence also was available from one RCT, but not all criteria were applicable. The WG had no 

serious concerns with risk of bias, but downgraded for indirectness because data were available 

for healthy persons, but not for persons with certain underlying conditions. Additionally, the 

intervention was an investigational MenABCWY vaccine, which was used as a proxy for the 

MenB-4C booster. The WG also downgraded for imprecision because the confidence intervals 

were wide due to the small number of subjects. For persistence of the immune response, the 

WG evaluated the same RCT and had the same conclusions about the quality of evidence for 

all criteria.

For SAEs, the WG evaluated evidence from one observational study. They had serious concern 

for risk of bias, as previously mentioned. The WG downgraded for indirectness because data 

were available for healthy persons, but not for persons with certain underlying conditions. The 

WG also downgraded for imprecision because the number of study subjects may be too small to 

detect rare events. In addition, the WG evaluated the same RCT and had the same conclusions 

about the quality of evidence for all criteria. The evidence type across these outcomes was a 4, 

indicating studies with important limitations, and the overall certainty of evidence was very low.

Moving on to the additional EtR considerations, from October 2014 through July 2018, 8% of 

persons aged at least 10 years with specific underlying conditions in commercial claims data 

received at least 1 MenB dose as part of the primary series. In comparison, 26% of these 

patients received at least 1 MenACWY vaccine. The low uptake in this group may reflect that 

the target population or their providers do not value the intervention, are unaware of the need 

for MenB vaccination, do not feel MenB vaccination is programmatically or financially 

acceptable, and/or encounter barriers that limit feasibility. In a survey of provider MenB 

vaccination practices, 81% of pediatricians and 56% of family physicians reported 

recommending the MenB vaccine for children aged at least 10 years at increased risk for 

serogroup B meningococcal disease, which may reflect their level of acceptance, awareness, or 

feasibility of MenB vaccination. Regarding resource use and cost, no published costeffectiveness analyses on the use of a MenB primary series or booster dose are available in this 

population. As far as feasibility, the data previously presented on MenB vaccine coverage and 

provider practices may signal feasibility challenges in implementing the MenB primary series 

recommendation. Consequently, feasibility challenges may be encountered for booster doses 

as well.

For this population at increased risk, serogroup B meningococcal disease is a problem of public 

health importance. The desirable effects of the MenB booster dose may vary in persons with 

underlying conditions versus healthy microbiologists. However, the undesirable effects are likely 

minimal, but safety data on multiple doses are not available. The intervention of the MenB 

booster dose is favored, but there is very low certainty of the evidence. The target population 

may feel uncertain that the desirable effects are large relative to undesirable effects, though 

there is important uncertainty in how much these persons value the main outcomes. A MenB 

booster dose is probably acceptable to key stakeholders, though it is uncertain whether the 

intervention is a reasonable and efficient allocation of resources or is feasible to implement.

Although the WG did not reach a full consensus on whether to propose a recommendation for 

persons with underlying conditions and microbiologists, the majority of its members was in favor 

of proposing a MenB booster recommendation for this population.

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Moving to the EtR for persons at risk during a serogroup B meningococcal disease outbreak, 

starting with stating the problem, serogroup B meningococcal disease outbreaks have occurred, 

accounting for 7% of all serogroup B cases in the US. Most of the organization-based serogroup 

B outbreaks are college-based, and 11 college-based serogroup B outbreaks were reported 

during 2013-2018. College students are the primary group at risk for these outbreaks who may 

have received a MenB primary series as healthy adolescents. While evidence presented here 

applies for all serogroup B outbreaks, all remaining data related to outbreaks are focused on 

college students.

Regarding benefits and harms of the MenB booster dose, including GRADE, no data are 

available on its effectiveness or duration of protection in US adolescents or adults. In the 4 

years following mass MenB-4C vaccination of persons aged <20 years during a regional 

outbreak in Canada, VE was estimated to be 79%, though the confidence interval was very 

wide. As far as indirect effects of the MenB vaccine, no evidence suggests that MenB vaccines 

reduce or prevent serogroup B meningococcal carriage, and therefore herd immunity is unlikely.

Regarding potential harms, evaluations following mass vaccination campaigns during outbreaks 

at US universities have demonstrated the safety of the MenB primary series.

For GRADE, the WG evaluated the same data that pertained to the other population of interest. 

For the MenB-FHbp booster, they evaluated data from an unpublished study by Pfizer. This 

observational study was an extension study, in which healthy persons received the MenB-FHbp 

booster dose 48 months after the MenB primary series. For the MenB-FHbp booster dose, the 

WG evaluated evidence for all outcomes from one observational study, though not all criteria 

were applicable. For all outcomes, the WG had serious concern for risk of bias, for the same 

reason previously mentioned. The WG had no serious concerns with indirectness, but 

downgraded for imprecision because the small number of subjects resulted in wide confidence 

intervals regarding persistence of the immune response and may not be able to detect rare 

SAEs. The evidence type across these outcomes was a 4, indicating studies with important 

limitations, and the overall certainty of evidence was very low.

Moving to the MenB-4C booster, data were available from three studies, which also were

evaluated for the other population of interest. The two observational studies were both 

extension studies. Short-term immunogenicity results were presented for each study separately, 

and data on SAEs were combined and analyzed as one study, as per the vaccine manufacturer.

The last study was an RCT in the US and Poland and was also an extension study. For the 

MenB-4C booster dose, the WG evaluated evidence for short-term immunogenicity from two 

observational studies. The WG had serious concern for risk of bias, for the same reason 

previously mentioned. They had no serious concerns with inconsistency, indirectness, or 

imprecision, and there were no other considerations. Evidence was available from one RCT, but 

not all criteria were applicable. The WG had no serious concerns with risk of bias, but 

downgraded for indirectness because the intervention was an investigational MenABCWY 

vaccine, which was used as a proxy for the MenB-4C booster. The WG also downgraded for 

imprecision because the confidence intervals were wide due to the small number of subjects.

For persistence of the immune response, the WG evaluated the same RCT and had the same 

conclusions about the quality of evidence for all criteria.

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For SAEs, the WG evaluated evidence from one observational study. They had serious concern 

for risk of bias, as previously mentioned. The WG had no serious concerns with indirectness, 

but downgraded for imprecision because the number of study subjects may be too small to 

detect rare events. The WG also evaluated the same RCT and had the same conclusions about 

the quality of evidence for all criteria. The evidence type was a 3 for the RCT across the 

outcomes and was a 4 for the observational studies, indicating RCTs with notable limitations 

and observational studies with important limitations. Thus, the overall certainty of evidence was 

low. 

In terms of the additional EtR considerations, all 11 universities that had serogroup B outbreaks 

implemented MenB vaccination, which demonstrates acceptability of MenB vaccination by key 

stakeholders. First-dose MenB vaccination coverage varied from 14% to 98% across these 

universities and may reflect the target population’s value and acceptability of MenB vaccines;

parents’ acceptability and encouragement for their children to receive MenB vaccine; feasibility 

concerns, especially at large universities; and differences in the student population, campus 

culture, and perceived risk of disease.

Despite acceptability from stakeholders, MenB mass vaccination requires substantial resources.

At one large university with approximately 20,000 undergraduate students, the total costs of 

vaccination were $1.7 million dollars, but the projected costs to achieve 100% primary series 

coverage were $7.7 million dollars. However, the strategy of MenB mass vaccination for 

outbreak response is estimated to be more cost-effective than universally vaccinating all 

students at college entry. Overall, the high costs incurred by universities may reflect the belief 

that these campaigns were a reasonable and efficient allocation of resources. Since the booster 

would require fewer doses than the primary series, it is anticipated that MenB booster doses will 

be viewed similarly.

In terms of feasibility, outbreaks require intensive coordination, significant human resources, 

and action among multiple stakeholders to efficiently respond within a short time. As MenB 

vaccines are not interchangeable, determining whether a MenB primary series was completed, 

the vaccine product, the date of the last dose, and ensuring availability of both MenB vaccines 

may impact feasibility during an outbreak. Universities have demonstrated the feasibility of 

conducting mass vaccination campaigns for the MenB primary series under challenging 

circumstances, so administering MenB booster doses is anticipated to be feasible as well.

For this population at risk during an outbreak, serogroup B meningococcal disease is a problem 

of public health importance. The desirable effects of the MenB booster dose may be large, with 

minimal undesirable effects. The intervention of the MenB booster dose is favored, but there is 

very low certainty of the evidence. The target population may feel that the desirable effects were 

large relative to undesirable effects, and there was probably variability in how much these 

persons value the main outcomes. The WG considered that the intervention of a MenB booster 

dose is acceptable to key stakeholders, a reasonable and efficient allocation of resources, and 

feasible to implement. Therefore, the WG proposed recommending a MenB booster dose for 

persons at risk during a serogroup B outbreak.

In summary, despite very low evidence quality, the majority of WG members favored MenB 

booster doses and proposed recommending this intervention for both populations at increased 

risk for serogroup B meningococcal disease. 

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WG Interpretation, Considerations for Policy Options, and Next Steps

Sarah Mbaeyi, MD, MPH 

CDC Lead, ACIP Meningococcal Vaccines WG 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Mbaeyi reviewed the WG’s interpretation of the persistence of the immune response 

following a MenB vaccine primary series and immunogenicity and persistence of a MenB 

booster dose, discussed the WG’s considerations for MenB booster doses in persons at 

increased risk for serogroup B meningococcal disease, and requested ACIP’s feedback on 

potential policy options for MenB booster doses. She began with persistence of the immune 

response following a MenB primary series, and reviewed the data for MenB-FHbp.

To summarize data for both a 3-dose and a 2-dose MenB-FHbp primary series from baseline

through 48 months post-primary series for each test strain, 2 studies measured seroprotection 

as the proportion of subjects who achieved an hSBA titer at or above the lower limit of 

quantification of the assay (either 1:8 or 1:16, depending on the strain), which is more 

conservative than the 1:4 threshold used in other studies presented earlier in the session. In 

these studies, initial antibody waning was observed 6 to 12 months following completion of the 

primary series, and then remained stable. Thus, the WG’s interpretation was that antibodies 

wane by 12 months following completion of a MenB-FHbp primary series, and then remain 

stable for up to 4 years in healthy adolescents [Adapted from: Marshall H, Lancet Infectious 

Diseases 2017 and Vesikari, Vaccine 2019].

Regarding data for MenB-4C, 4 studies were conducted to assess immunogenicity and 

persistence to each of the 4 vaccine antigens through 7.5 years post-primary series. The WG 

was particularly interested in the results for FHbp and NHBA, as these antigens contribute most 

to strain coverage in the US. Because the study populations and time points assessed were 

different for the various studies, and generally speaking, antibody waning patterns for the 4 

antigens were not consistent, Dr. Mbaeyi walked through each study in more detail.

A study in UK adolescents demonstrated a high proportion of subjects with seroprotection at 11 

months following completion of the primary series. However, baseline antibody titers were high 

in this study, reaching nearly 70% for FHbp, and no data were available for NHBA. In a study 

from Chile, evidence of persistence through 18 to 23 months was observed, though subjects in 

this study also had elevated baseline titers. Although a substantial proportion remained 

seroprotected by 7.5 years, this proportion was not significantly different than baseline titers for 

most of the antigens. The WG felt that the US/Poland study and the Canada/Australia study

were most representative of the US context.

In the US/Poland study, antibody waning was evident by 2 years following completion of the 

primary series, though confidence intervals were wide, with relatively consistent results by 4 

years in the Canada/Australia study for most antigens. Persistence following a MenB-4C 

primary series was difficult to generalize due to the heterogenous results by vaccine antigens, 

different time points assessed in different studies, elevated baseline titers in two studies, and 

limited persistence data for NHBA. In light of this, the WG’s interpretation was that antibodies

wane by 2 years following the primary series in healthy adolescents and adults, though they 

may wane earlier [Adapted from Read RC, Vaccine 2017; Block SL, Vaccine 2015; Szenborn L, 

Pediatr Infect Dis J. 2018; Perrett KP, Vaccine 2015; Nolan T, Vaccine 2019; Santolaya ME, 

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Lancet 2012; Watson PS, Expert Review of Vaccines 2019, and results on clinicaltrials.gov; * 

hSBA titer of 1:5 used in US/Poland study].

In summary, given the variable rate of waning between vaccine types and between studies, 

antibody persistence following a MenB primary series could not be generalized. It also must be 

noted that the two vaccines are completely different, and evaluations of immunogenicity and 

persistence were conducted using different strains and immunologic endpoints, and thus cannot 

be directly compared. However, the WG felt that by 1 to 2 years following a MenB primary 

series, booster vaccination is indicated for persons who remain at increased risk.

Regarding immunogenicity and persistence of a MenB booster dose starting with MenB-FHbp, 

immunogenicity and persistence of a booster dose 4 years after completion of either a 2 or 3 

dose primary series demonstrates a robust immune response at 1 month with gradual waning 

and evidence of persistence through 26 months post-booster dose. Thus, the WG’s assessment 

was that the immune response to a MenB-FHbp booster dose persists for at least 2 years in 

healthy adolescents, and given the gradual antibody decay pattern, may last longer [Adapted 

from Pfizer data presented to ACIP meningococcal WG].

For MenB-4C, regardless of timing since completion of a MenB-4C primary series (whether 2, 4, 

or 7.5 years), a robust immune response was demonstrated 1 month post-booster. No studies 

assessed persistence of a MenB-4C booster dose. However, following a MenABCWY booster 

dose in the US/Poland study, antibody persistence was observed through 12 months postbooster. Thus, the interpretation of the WG was that the immune response to a MenB-4C 

booster dose likely persists for several years in healthy adolescents and adults. This 

interpretation was primarily derived through demonstration of good persistence of a 

MenABCWY booster dose through 12 months and modeled data presented earlier in this 

session by GSK suggesting persistence for several years. However, no further precision in the 

estimate was possible due to the lack of observed data [Adapted from Szenborn L, Pediatr 

Infect Dis J. 2018; Nolan T, Vaccine 2019; Watson PS, Expert Review of Vaccines 2019;* hSBA 

titer of 1:5 used in US/Poland study].

To summarize, a MenB booster dose elicits a strong immune response, and the persistence 

appears to exceed that of a MenB primary series. Thus, the WG’s interpretation was that 

antibody persistence of a MenB booster dose is likely at least 2-3 years, and may be longer, in 

healthy adolescents and adults.

To summarize the WG’s deliberations for MenB booster doses in persons at increased risk, Dr. 

Mbaeyi first explained why the WG is reviewing policy considerations for MenB booster doses at 

this time. ACIP recommended a MenB primary series for persons at increased risk 4 years ago

during the February 2015 meeting. Starting in late 2018, several cases of serogroup B 

meningococcal disease were reported in fully vaccinated people, both in healthy persons and 

those with underlying conditions. Strain coverage analysis is still ongoing to assess whether 

these cases should have been averted through vaccination. Regardless, the WG expects future 

breakthrough cases to occur, and thus felt it was time to start considering MenB booster doses.

In addition, serogroup B outbreaks among college students continue to occur. As MenB 

vaccination coverage in healthy adolescents increases under the Category B recommendation, 

an increasing number of vaccinated college students will be exposed during an outbreak.

Finally, both vaccine manufacturers have indicated that no further data are forthcoming. 

Additional data on effectiveness and duration of protection may take years to generate. Thus, 

the WG moved forward on reviewing data on the persistence of the immune response following 

a MenB primary series, and immunogenicity and persistence of a MenB booster dose. The WG 

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did not reach a consensus on either the need for or timing of MenB booster doses. A minority of 

WG members felt there was insufficient evidence on safety and efficacy of MenB booster doses 

to inform policy options. However, the following represents the views of the majority of WG 

members.

In terms of the need for MenB booster doses, the WG’s primary consideration was that 

meningococcal disease is a devastating infection and the groups at increased risk represent 

small, targeted populations. Available evidence suggests waning of the primary series, and a 

booster dose elicits a robust immune response. However, this is based on hSBA titers, which is 

the serologic correlate of protection, but may not accurately represent the level of expected 

clinical protection. In summary, the WG felt that MenB booster vaccination is necessary to 

sustain protection in persons who remain at increased risk.

Studies reviewed by the WG indicate antibody waning by 1-2 years following the primary series, 

and persistence of a booster dose for at least 2 years and likely longer. However, 

immunogenicity and persistence of MenB vaccination may be limited in persons with underlying 

conditions, especially those with complement deficiency or complement inhibitor use. Thus, the 

WG suggested that a MenB booster dose is indicated at 1 year following completion of the 

primary series. Greater persistence is expected after the booster dose, and thus, a longer 

interval for repeat booster doses may be considered. Clinical trials and other observational 

studies have demonstrated the safety of the MenB primary series. Limited data are available on 

booster doses, though no SAEs have been reported. There are no data on safety in persons 

with underlying conditions, and no data on repeat booster doses. Despite this, given the serious 

nature of meningococcal disease, the WG felt that the potential benefits of MenB booster 

vaccination outweigh potential risks in this population.

The WG also discussed programmatic considerations for MenB booster doses. While 

harmonization with MenACWY is desired, the WG felt that the data do not support a 5-year

interval for MenB booster doses, and thus, harmonization is not the main priority. Additionally, 

the WG felt that the booster dose recommendations for MenB-FHbp and MenB-4C should be 

harmonized to minimize unnecessary complexity in booster dose schedules. Outbreak 

situations come with additional challenges, and booster dose eligibility may be difficult to rapidly 

determine. Additional clinical guidance, such as updated language in CDC’s outbreak guidance, 

will be necessary to facilitate booster dose implementation.

Based on these deliberations, the WG considered potential MenB booster policy options for 

persons at increased risk. In persons at increased risk due to certain underlying conditions or 

occupational exposure, the WG felt that the available data supported an initial 1 year booster 

dose followed by repeat booster doses every 2-3 years. This conservative approach was felt to 

be reasonable in order to maximize protection in persons in whom immunogenicity and 

persistence may be reduced, or in microbiologists who may experience increased exposure.

The WG also felt that allowing a flexible range of every 2-3 years would allow for some 

harmonization for meningococcal booster doses, as both a MenACWY and MenB booster dose 

could be given together every other time, which may reduce missed opportunities for 

vaccination. However, there are some potential downsides to this more complicated schedule, 

which may be more conservative than necessary.

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The WG also considered a standard interval such as every 2 or 3 years, as it is more 

straightforward and prescriptive, but WG members felt that this may leave the target groups with 

insufficient protection for greater periods of time. During serogroup B outbreaks, the majority of 

WG members favored a booster dose if it has been at least 6 months since completion of the 

primary series in order to boost immunity prior to antibody waning, thus maximizing individual 

protection during a short-term period of increased exposure. However, this is a more 

conservative approach than that proposed for other persons at increased risk, without 

substantial evidence to support this distinction. Additionally, a 6 month interval may send an 

inaccurate message on duration of protection of MenB vaccines, leading to reduced vaccine 

confidence. Thus, a 1 year interval also was considered, as most people are expected to have 

protective antibodies through 1 year post-primary series, though there may be some who do 

not. Additionally, a minimum 1 year interval would be consistent with the proposed booster 

interval for other groups at increased risk. Regardless, the WG favored flexibility given the 

unique circumstances of each outbreak.

Given these considerations, the WG requested ACIP’s feedback on these potential policy 

options:

❑

❑

For persons with complement deficiency, complement inhibitor use, asplenia or microbiologists, a MenB 

booster dose 1 year following completion of a MenB primary series, followed by MenB booster doses every 

2-3 years thereafter, for as long as increased risk remains.

For persons at increased risk during an outbreak, a one-time MenB booster dose is recommended if it has 

been ≥1 year since completion of a MenB primary series. A booster dose interval of ≥6 months may be 

considered by public health officials depending on the specific outbreak, vaccination strategy, and projected 

duration of elevated risk.

The WG expressed interest in hearing ACIP’s feedback on the WG’s interpretation for the need 

and timing of booster doses, including whether the booster dose interval should be the same for 

both vaccines and whether there were any additional data ACIP would like to see. Based on 

ACIP’s feedback, the WG planned to present policy options for a vote during an upcoming ACIP 

meeting.

Discussion Points

Dr Talbot asked whether both of these vaccines are T-cell independent; that is, just because the 

antibodies wane, does that mean that there is no T-cell response or does T-cell response take 

too long? In addition, it appeared that at least 1 antigen was similar between the two vaccines. If 

so, she wondered if a trial could be conducted giving the alternate vaccine as a booster. She 

was trying to visualize a college campus trying to purchase vaccine and vaccinate, and trying to 

figure out which vaccines they had previously.

Dr. Stephens indicated that these vaccines do induce some memory response, which is what 

the booster is showing. There is a feeling that memory alone will not protect against 

meningococcal disease because of the short incubation period within 7 to 10 days of 

acquisition.

Dr. Mbaeyi indicated that both vaccines contain fHbp. One of the major challenges to feasibility 

is that the vaccines are not interchangeable. The WG recognizes that this is going to be one of 

the major challenges, and it is a major challenge for the primary series as well.

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Dr. Szilagyi said he supported the WG suggestions. For patients with complement deficiencies 

or asplenia, data were presented about “values” based on the low vaccination rate. However, he 

suggested that those were not really data about values. Most of these patients are also taken 

care of by pediatric subspecialists. Data also were presented that 81% of pediatricians favor 

vaccinating these patients. He thought this was more of a rollout or lack of information rather 

than a concern about values.

Dr. Atmar expressed concern about the booster data in that the intervals of when the boosters 

have been given were longer, at least for the first vaccine discussed, than what was proposed. 

At least with other vaccines, the interval of boosting can affect the magnitude of response. The 

concern is a reasonable one, and it sounded like they would have to make a decision without a 

lot of data. He would be interested in knowing whether any additional information would be 

available by June about apparent vaccine failures in terms of the strain and duration of time 

from completion of primary series to infection, in order to get some idea of when these failures 

occurred and if the proposed intervals make sense in light of those kinds of data.

Dr. Mbaeyi indicated that the WG does anticipate having more information available in the 

coming months and could present an update. They wanted to at least signal this issue to ACIP, 

though they did not have all of the information yet related to the strain coverage, underlying 

conditions, et cetera. It is something the WG can prepare.

Dr. O’Leary (PIDS) said his understanding was that serogroup B is not usually the issue for 

immunocompromised patients, and asked what the burden of disease is in that population in the 

last several years.

Dr. Mbaeyi replied that they did not present these data because they do not have great 

information at this point. Some of this information is collected historically through ABCs, which 

represents less than 15% of the population. Meningococcal disease is so rare right now that it is 

not going to be very representative and is a small number. Some additional information has 

been collected through enhanced meningococcal disease surveillance for the past couple of 

years. Through more in-depth chart reviews for ABCs, it has been observed that few patients 

report having complement deficiency tested for, let alone a diagnosis. Thus, they are not 

confident that this information is being captured through the surveillance mechanisms. There 

just is not a great estimate on the number of cases and their serogroup distribution at this time.

Dr. Walter wondered in an outbreak situation under what conditions a 6-month interval would be 

utilized versus 1 year and how that would play out in the outbreak by public health officials.

Dr. Moore responded that it is known that this vaccine has less impact on nasal carriage than 

MenACWY does, and there has been evidence of breakthrough disease occurring in people 

after mass vaccination on a college campus. One of the outbreaks included a case and a visitor 

that occurred after everyone else was vaccinated because the strain was still circulating. The 

concern was for an outbreak starting at the beginning of a school year among a population who 

is 10 or 11 months out from their primary series and whose increased risk of exposure may 

occur throughout the entire school year, as opposed to an outbreak identified at the end of a 

school year right before everyone disperses. There are also questions about how easily records 

can be obtained, and how strict they want to be about a 1-year interval. It was the incredibly 

specific practical operational considerations that could come into play that might result in a 

campus opting to conduct only one mass vaccination campaign. That is the reason that it says it 

should be considered by public health officials as opposed to individual clinicians.

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Dr. Zahn (NACCHO) pointed out that while thinking through how to vaccinate thousands of 

students in a school and figuring out who should receive a booster when there has been a 

potential exposure is complicated. However, it already is pretty complicated. Either they 

vaccinate everyone and inadvertently vaccinate some people with the wrong booster, or they 

get aggressive in making sure it is exactly correct and will vaccinate a lot less because they will 

not get their vaccination schedule.

Dr. Maldonado (AAP) pointed out that AAP has struggled with the Category B recommendation 

as it is for healthy children. In terms of persons at increased risk during an outbreak, this puts 

healthy people into an at-risk group. That is a huge step and raised questions about how those 

risk groups will be defined. Do they fall under risk only during outbreaks? If they are backing that 

definition out, does that mean everybody should be considered at risk if they are going to 

college? She thought they already had dealt with that issue in terms of the very small numbers 

of cases in that age group, half of whom are not even in college. She emphasized that this 

needs to be very clearly defined, because pediatricians are struggling with this. While 7% 

coverage was mentioned for the first category at risk, she wondered about the percentage of 

coverage for persons at increased risk during an outbreak or in healthy children otherwise. 

Following up on the previous question, it seemed that if someone knows they have been 

immunized, they should get a booster during an outbreak. It was not clear to her how they were 

going to differentiate this, especially in the midst of a large outbreak.

Dr. Mbaeyi indicated that the coverage data based on NIS-Teen suggest that about 14.5% of 17 

year olds have received at least 1 dose of MenB vaccine. There is no information from that 

survey regarding series completion, but other sources of data suggest that 50% or less so far 

have actually completed a series who have started it. It is low, but has been steadily increasing 

since the recommendation was made. They do not have any information on coverage 

specifically among college students. They expect that it is probably higher than for the general 

adolescent population. What they mean for this group is people who have been identified by 

public health officials to be in the at-risk group during an outbreak. In most of the university 

outbreaks that have occurred so far, it has been all undergraduate students. Those are 

decisions that are not part of the ACIP language. Public health officials make the determination 

of what groups are at-risk during an outbreak, then vaccination recommendations are made and 

there is outbreak guidance.

Dr. Messonnier indicated that a representative from AAP is on the WG. Perhaps AAP could help 

CDC work offline through how they might suggest addressing this. The clinical difficulty is 

clearly recognized, but there also is the issue regarding the data on waning immunity.

Dr. Bernstein asked whether there are any data about the use of vaccine type. Given that the 

vaccines are not interchangeable, he wondered what data colleges are collecting in terms of the 

specific products that have been received by their students.

Dr. Mbaeyi indicated that what they have heard from their colleagues in college health, including 

those on the WG, is that a lot of colleges do not have this information readily at their disposal. 

MenB vaccination is not mandated by most universities at this time, so there is very little recordkeeping and it is a challenge during an outbreak to know vaccine status. That is true even for 

the primary series.

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Dr. Bernstein said he understood that a growing number of colleges are requiring MenB 

vaccine, and he wondered whether it should be more explicit in terms of which product is being 

received. He also understood that an increasing number of camps are requiring receipt of MenB 

vaccine before attending camp, beginning at the age of 10.

Dr. Even (ACHA) confirmed that it is true that there is not a good record. Very few schools 

require MenB vaccines. They receive vaccination records for students, so that information is 

known. However, the students do not know what they have had. The records are typically in a 

scanned database or otherwise not easily accessible when an outbreak occurs. There is 

variability of entering students in terms of MenB vaccine, but there are definitely more entering 

students who have been vaccinated than before. Knowing that a campus may experience an 

outbreak at some later point and since immunity wanes, the outbreak recommendation is still 

the strongest one. The ability to mobilize is important even though it is so difficult, but it happens 

so infrequently that having public health recommendations to identify the smallest group at the 

earliest opportunity to begin vaccination is feasible. In a prolonged outbreak, there are really just 

2 months in which the 6-month parameter would fall, June and July. Otherwise, it would be 

during the months classes are in session.

Introduction

Kelly Moore, MD, MPH 

ACIP Chair, Zoster WG 

Vanderbilt University School of Medicine 

Dr. Moore reminded everyone that in October 2017, ACIP made the following 

recommendations:

1) Recombinant zoster vaccine (RZV, SHINGRIX) is recommended for the prevention of 

herpes zoster and related complications for immunocompetent adults aged ≥50 years.

2) RZV is recommended for the prevention of herpes zoster and related complications for 

immunocompetent adults who previously received zoster vaccine live (ZVL, [Zostavax]).

3) RZV is preferred over ZVL for the prevention of herpes zoster and related complications. 

Its publication in 2018 was a supplement to the existing recommendations for the use of ZVL in 

immunocompetent adults aged ≥60 years [Dooling et al. MMWR Jan 25, 2018].

Since June 2018, there have been 6 WG meetings during which the following topics were 

discussed:

❑

❑

❑

Burden and pathophysiology of herpes zoster in immunocompromised persons

RZV vaccine performance in immunocompromised persons

Post-licensure safety and uptake monitoring of RZV

Zoster Vaccines

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Dr. Moore indicated that the presentations for the February 2019 session would focus on the 

preliminary results of RZV safety and uptake.

Update on Post-Licensure Safety Monitoring of RZV (SHINGRIX)

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office 

Centers for Disease Control and Prevention 

Dr. Shimabukuro reminded everyone that RZV is an adjuvanted glycoprotein vaccine that was 

reactogenic in clinical trials, with rates of SAEs similar between RZV and placebo groups. He 

also clarified a few of the terms that are used in the context of vaccine safety monitoring and 

research, which are shown in the following table:

This session focused on post-licensure safety monitoring of RZV during initial uptake period

based on data from Vaccine Adverse Event Reporting System (VAERS) monitoring and 

preliminary results from the Vaccine Safety Datalink (VSD) Rapid Cycle Analysis (RCA).

VAERS is a national passive surveillance system for AE that is co-managed by the CDC and 

FDA. The strengths of VAERS are that it can rapidly detect safety signals and can detect rare 

AEs. It is subject to the limitations of spontaneous reporting in general. Reports of AEs are 

received in VAERS, some of which may be true AEs and some of which may be coincidental 

events and not related to vaccination. All reports are accepted without judging causality or the 

seriousness of the event. Because of the limitations, generally causality cannot be assessed 

from VAERS data as it is a hypothesis generating system. During this session, Dr. Shimabukuro

presented an update on the publication titled Postlicensure Safety and Surveillance of 

Recombinant Zoster Vaccine (Shingrix)—United States, October 2017-June 2018.

The descriptive analysis Dr. Shimabukuro presented included all RZV reports received from

October 20, 2017 through December 31, 2018. Reporting rates were calculated based on doses 

distributed in the US market. CDC’s colleagues at FDA conducted an Empirical Bayesian (EB)

data mining to detect disproportional reporting for VAE pairings. Reports were clinically 

reviewed, including medical records when available, for 22 pre-specified outcomes listed here 

alphabetically:

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During the analytic period, 14,381 reports were received following RZV. Of those, 97.6% were 

classified as non-serious. Based on 8.59 million doses distributed during this period, the 

reporting rate for all reports was 167 per 100,000 doses distributed and 4 per 100,000 for 

serious reports. Those rates are similar to what is observed for other vaccines administered in 

this age group. A serious report is defined by the Code of Federal Regulations (CFR) as “death, 

life-threatening illness, hospitalization, or prolongation of hospitalization or permanent disability.” 

Again, these are reports occurring in temporal association and no judgement is being made on 

causality.

Systemic signs and symptoms and injection site reactions were the most commonly reported 

AEs. No unexpected patterns were detected by physician reviewers of reports of the 22 prespecified outcomes. EB data mining detected one finding, which was a “product administered to 

patient of inappropriate age” when looking at individuals aged 19-44.9 years old, an age group 

for which RZV is not approved.

In summary, RZV post-licensure safety monitoring findings in VAERS are generally consistent 

with the safety profile observed in pre-licensure clinical trials. Self-limited systemic signs and 

symptoms and injection site reactions were the most commonly reported AEs. SAEs were rarely 

reported at 2.4% of reports, which is similar to other vaccines given in the same age group.

There were no EB data mining findings for any RZV-AE pairings except for “product 

administered to patient of inappropriate age.”

Moving to the VSD RCA for RZV, the VSD is a collaboration between CDC and several 

integrated healthcare plans. It is a large linked database that is used for surveillance and 

research. Vaccination records, health outcomes, and patient characteristics are linked by unique 

patient IDs. RCA is a powerful and sophisticated tool for near real-time vaccine-safety 

monitoring. It is a surveillance activity, which is not the same as an epidemiologic study. It 

requires careful thought and customization in the design, set-up, and interpretation. It employs 

an automated analysis that uses ICD-coded diagnoses from claims data. It is designed to detect 

statistical signals (e.g., values above specified statistical thresholds). Not all statistical signals 

represent a true increase in a risk for an AE. When a statistical signal occurs, CDC conducts a 

series of evaluations using traditional epidemiologic methods. Chart-confirmation of diagnoses 

to confirm or exclude cases as true incident cases is a key part of statistical signal assessment.

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The primary analysis for RZV RCA is a historical comparator design. Monthly near real-time 

sequential monitoring of pre-specified outcomes is done. There will be 18 planned monthly 

analyses, which began at 6 months after January 2018, with an 18-week data lag. This data lag 

accounts for the risk windows plus time to let the claims data settle and mature. As mentioned, 

this is an automated analysis using ICD-10 or ICD-9 codes depending upon the dates. The third 

analysis has been completed, and the test statistic is an adjusted likelihood ratio test. Observed 

events are compared in one risk window for current recipients to what is expected for the 

historical ZVL recipients from 2013-2017. There are 10 high priority pre-specific RZV RCA 

outcomes:

High Priority Pre-Specified Outcomes* Risk Interval (Days)

 Acute myocardial infarction 1-42

 Anaphylaxis 0-1

 Bell’s palsy 1-42

 Convulsion 1-42

 Giant cell arteritis 1-42

 Guillain-Barré syndrome 1-42

 Optic ischemic neuropathy 1-42

 Polymyalgia rheumatica 1-42

 Stroke 1-42

 Supraventricular tachycardia 1-42

*Footnote: gout, keratitis, local reactions, non-specific adverse effects, 

pneumonia, systemic reactions, uveitis and retinitis, and zoster ocular disease

There also are other outcomes for descriptive analysis only, including those listed in the 

footnote of the table. These outcomes are based on outcomes of historical concern for vaccine 

safety, plus outcomes that were described in the pre-licensure submissions to FDA, plus 

outcomes monitored for ZOSTAVAX® as well.

Secondary analyses for RZV RCA in the VSD uses 2 concurrent comparators, including 

individuals who: 1) had an ICD-10 coded well-visit during the RZV uptake period; or 2) 

received some other vaccine (e.g., for pneumonia, Td, Tdap, IIV) during the RZV uptake period. 

For the third analysis, roughly 106,000 doses were administered through August 2018. The 

follow-up for outcomes is through December 2018. For 9 of the high priority outcomes, there 

was no preliminary statistical signal (e.g., no evidence of an increased risk). There was one 

preliminary statistical signal for Guillain-Barré Syndrome (GBS), which was detected initially 

during the second analysis. In the third analysis, there were 4 observed GBS events in the risk 

interval compared to 0.8 expected events for a relative risk of 5.06. The likelihood exceeded the 

critical value, so this is a statistical signal. When there is a statistical signal, one of the first steps 

is to conduct a [chart review]. One of the major activities in the RCA is to review those cases in 

the VSD. Here is a table with a short chart review of automated cases: 

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The short chart review is not the full clinical narrative. It is basically an abbreviated review in 

which key data are extracted to allow for a rapid assessment of the cases. The first two cases 

are individuals with a history of GBS diagnosed years prior. There is no recurrence or 

exacerbation after RZV. An incident case is a case that is either new in general, or new onset 

during the specified time period. These cases were diagnosed years in the past and then 

appeared because there was some type of health encounter after vaccination during which this 

was captured in the VSD database.

The third case was a 68-year old female who received concurrent PCV13 and had ZVL 7 years 

prior, with GBS onset 13 days post-vaccination and was hospitalized 15 days post-vaccination. 

The short chart review confirmed this case, which was classified as Brighton Criteria Level 2. 

Brighton is a standardized case definition used in vaccine safety, with 1 being the highest level 

of diagnostic certainty. The fourth case was a 59-year old female who received concurrent 

HepB vaccination and had chart documented GBS onset no later than 1 day post-vaccination. 

The symptoms may have started prior to vaccination, as the patient had some signs and 

symptoms in the month prior and days leading up to vaccination suggestive of an infection, such 

as respiratory and gastrointestinal (GI) symptoms. This was adjudicated as a short chart review 

confirmed case, Brighton Criteria Level 1, with actual [timing of] GBS onset symptoms being 

uncertain.

After the initial chart review of these cases, 2 were ruled out, 1 appeared to be a confirmed case 

in the risk window, and the last case was confirmed but questionable because GBS symptom 

onset is uncertain. Even if it was 1 day, that is a pretty short onset after an exposure for GBS. It 

is important to note that a case in the risk window does not equate to a causally associated 

case. It means there was a vaccination and then a case in the risk window that fell within this 

window of biological plausibility.

In summary, after the third analysis of 18 planned analyses, there have been 106,121 doses of 

RZV administered in VSD from January-August 2018. There is no evidence of increased risk for 

any of the pre-specified outcomes except GBS in the automated ICD-10/9 analyses. A statistical 

signal for GBS was detected in the primary analysis and consistently elevated relative risks 

across other comparators: RR=5.06 for ZVL comparators, RR=2.95 for well-visit comparators, 

and RR=3.25 for received some other vaccine comparators. Full clinician narratives have been 

requested for review for the 2 valid GBS cases (i.e., symptoms and onset, physical findings, 

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relevant testing, physician assessments, et cetera). There also are plans to chart review the 

GBS cases following ZVL in the historical comparator group.

Part of the signal assessment was to re-review the VAERS reports for GBS. There were 35 

reports that had a MedDRA Preferred Term (PT) for GBS assigned. Upon review, 19 case 

reports met Brighton criteria for GBS level 1 (1), level 2 (15), or level 3 (3). Of the case reports, 

6 did not meet Brighton criteria or had insufficient information, but were explicitly described as 

physician-diagnosed GBS. The remaining 10 reports did not meet Brighton criteria and were not 

physician diagnosed. Of the 25 cases that met Brighton criteria levels 1-3 or were physician 

diagnosed, 24 had symptom onset within a 0-42 day risk window following RZV. That translates

into a reporting rate of 2.8 GBS cases per million RZV doses distributed.

Proportional Reporting Ratio (PRR) analyses also were performed that did not detect any 

disproportional reporting for RZV-GBS when either ZVL, IIV, or PPSV23 vaccines were used as 

comparators. This is similar to FDA’s EB data mining in terms of looking at disproportionality or 

disproportional reporting. Looking at comparator groups of specific vaccines, no disproportional 

reporting was detected for RZV GBS when either ZVL, IIV, or PPSV23 were used as 

comparators.

In terms of next steps, FDA is exploring options for an analysis of GBS following RZV in the 

Center for Medicare and Medicaid Services (CMS) database. CDC will continue to monitor this 

preliminary VSD RCA statistical signal for GBS following RZV by tracking additional counts of 

GBS, and will continue enhanced monitoring for RZV in VAERS to include clinical review of all 

GBS reports following RZV. In terms of the timeline, this signal was detected in November 2018 

and rapidly evaluated. Colleagues in the immunization program and FDA were notified, and the 

ACIP Zoster WG was engaged and heard presentations twice in February 2019, and during this 

meeting.

In closing, this is still the initial uptake period for RZV and early in the post-licensure monitoring 

process. Overall, the safety profile of RZV is consistent with pre-licensure clinical trial data. The 

VAERS data indicate that systemic and local reactions are commonly reported, with no findings 

of disproportional reporting for GBS or any other pre-specified outcomes. A limited number of 

doses have been administered in the VSD at this point. A statistical signal was detected in the 

VSD RCA based on a small number of GBS cases using automated data. There are currently 4 

ICD-10 coded GBS cases. Upon review, there is 1 confirmed case in the risk interval, 1 

confirmed case with questionable onset timing and possible infectious trigger, and 2 historical 

cases that have been ruled out. The post-licensure safety monitoring systems and surveillance 

methods are designed to be rapid, sensitive, and allow for quick assessment of statistical 

signals. The policy is to be transparent and communicate vaccine safety information in a timely 

manner. These preliminary data are insufficient to conclude that a safety problem exists for 

GBS, but further evaluation and continued vigilance are warranted. The RZV-GBS statistical 

signal detection and assessment demonstrates the robust and responsive US vaccine safety 

monitoring system in action, working as intended. CDC will update the Zoster WG as 

information comes available and will be available to update ACIP as requested.

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Herpes Zoster Vaccines Update

Dr. Kathleen Dooling MD MPH 

Herpes Zoster Work Group Liaison 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Dooling reminded everyone that during the June 2018 ACIP meeting, she showed a table 

summarizing CDC’s plan for monitoring RZV coverage, uptake, and 2-dose series completion. 

During this meeting, she planned to present preliminary data from 3 of those systems including: 

1) data from the Immunization Information Systems (IIS) in 6 jurisdictions; 2) vaccine 

administrative claims data from Medicare beneficiaries and CMS; and 3) VSD data (presented 

by Dr. Dr. Shimabukuro).

In terms of the preliminary results for RZV uptake in IIS, the observation period for this analysis 

was October 17, 2017 through December 31, 2018. Data were contributed from 6 jurisdictions: 

Minnesota, Michigan, Oregon, North Dakota, Wisconsin, and New York City. The inclusion

criteria for analysis were age ≥50 years and a record of at least one RZV vaccination dose 

within the IIS during the observation period. Data were pulled between February 7-14, 2019 and 

are dynamic; that is, reports may still be received within the system. The analysis provided by 

IIS Sentinel Site awardees in each jurisdiction. A total of 751,405 doses of RZV were reported in 

IIS during the study timeframe. Of those, 21% (155,594) of those doses were administered to 

persons 50-59 years of age, 41% (304,365) were received by persons 60-69 years of age, 28% 

(210,487) were received by people 70-79 years of age, and 11% (80,959) were received by 

individuals 80 years of age and older.

Looking at the number of RZV doses recorded in IIS by month from October 2017 through 

December 2018, the doses administered increased sharply in March and April. After that, 

between approximately 60,000 and 100,000 doses were administered each month in these 

settings. Regarding the proportion of RZV administered in pharmacy versus non-pharmacy 

settings, a minority (39%) of people in their 50s were vaccinated in a pharmacy. That proportion 

increases to 54% for people in their 60s, and to a full 70% of people in their 70s and 80s. It 

should be noted that these estimates varied substantially by state, ranging from 28% overall in 

one jurisdiction to 85% in another. However, in all jurisdictions older age was associated with 

increased chance of being vaccinated in a pharmacy setting.

With regard to preliminary results for RZV uptake among Medicare beneficiaries, similar to the 

previous analysis, the observation period was October 1, 2017 through December 31, 2018. 

The inclusion criteria for beneficiaries was that they had to age into Medicare by October 2017 

and that they were continuously enrolled in Medicare Part D from October 2017 to vaccination 

date. Data were pulled during February 13-14, 2019 and the data are dynamic. This analysis

was provided by Acumen, LLC through a collaboration with FDA, CMS, and CDC.

In terms of the characteristics of Medicare beneficiaries who received at least one dose of RZV, 

in this analysis over 1.5 million beneficiaries were vaccinated with RZV under Medicare Part D. 

The mean age was 75 years, the vast majority were younger than 80 years of age, and 59% 

were female.

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Regarding the number of ZVL and RZV vaccinated Medicare beneficiaries by month during the 

analysis time period, ZVL administration declined toward the end of 2017. The first dose of RZV 

began to rise steeply in March and April, with the second dose increasing 3 months later in June 

and July. As mentioned, just over 1.5 million beneficiaries received the first dose and over 

750,000 received a second dose during the same time period.

The second dose of RZV is recommended 2 to 6 months following the first dose. This table 

shows RZV series completion and timing of the second dose for Medicare beneficiaries 

vaccinated in 2018:

Month of First RZV 

Vaccination

Number of Beneficiaries 

With First Vaccination

Proportion of Vaccinated Beneficiaries Who Have Received Second 

Vaccination (Cumulative Time Since Vaccination)

2nd month

(60 Days)

3rd month

(90 Days)

6th month

(180 Days)

9th month

(270 Days)

Jan 2018 11,217 8% 47% 78% 86%

Feb 2018 32,412 7% 43% 77% 85%

Mar 2018 89,471 4% 37% 76%

Apr 2018 196,464 3% 31% 77%

May 2018 202,537 2% 33% 76%

Jun 2018 153,839 3% 35%

Jul 2018 135,398 3% 32%

Aug 2018 175,008 2% 29%

Sep 2018 188,710 3%

Oct 2018 149,585

Nov 2018 103,033

Dec 2018 87,037

As reflected in the table in the highlighted box, at least 75% of beneficiaries for whom at least 6 

months had elapsed received the second dose. This is strong series completion despite 

challenge with shortages of RZV. It also must be taken into account that these Medicare 

beneficiaries are highly motivated vaccine seekers who received the first dose within the first 5 

months of CDC recommendations when the vaccine supply was just becoming available.

Moving on to RZV status, GSK plans to manage RZV supply by continuing order limits during 

2019. Therefore, providers will continue to experience shipping delays. In response to demand 

for the vaccine during 2018, GSK has taken two steps. The first was to increase the number of 

doses available for the US market in the second half of 2018. The second was to plan for more 

frequent, higher volume shipments to increase supply and deliver doses more consistently for 

all customer types during 2019.

In conclusion, the following points summarize the HZ WG discussions. RZV demand continues 

to outpace supply. Approximately 8.59 million doses were distributed in the US through 2018, 

with a greater number of doses expected in 2019. The 2-dose RZV series completion within 6 

months was >75% among Medicare beneficiaries. While this is strong series completion, it is 

important to continue monitoring as the supply stabilizes and immunization providers can 

expand their reach beyond the most highly motivated vaccinees. A preliminary statistical signal 

for GBS among RZV recipients has been observed based on 4 claims in administrative data. 

Because claims data are not medical records, they require verification and investigation. In fact, 

in a brief chart review, it was confirmed that onset of GBS predated receipt of RZV in 2 cases. 

The HZ WG agreed that there is insufficient evidence at this time to support a change in 

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policy or practice. More investigation is required to determine whether this statistical signal is or 

is not a safety problem. In order to do that, clinical validation is necessary and is underway. 

Evaluation also is needed of near real-time data in multiple systems, which also is underway. 

The HZ WG will be updated on each step as soon as information becomes available. The WG 

commits to reporting interpretation of those data to ACIP at the earliest opportunity.

Discussion Points

Dr. Leonard Friedland (GSK Vaccines, Medical Affairs) emphasized that GSK’s top priority is 

patient safety and GSK is committed to monitoring and assuring the safety of all of its products, 

including SHINGRIX. GSK recognizes the importance of the VSD and a comprehensive review 

of pre-clinical studies, clinical trials, and post-marketing reports to GSK have not indicated an 

increased occurrence of GBS following vaccination with SHINGRIX. GSK remains confident the 

favorable benefit-risk profile of SHINGRIX for the prevention of herpes zoster (HZ), and GSK 

will continue to work closely with the CDC and the FDA to actively monitor the safety of 

SHINGRIX.

Dr. Hunter inquired as to whether the definition of the risk window started for RZV with the first 

or second dose.

Dr. Shimabukuro indicated that the risk windows for dose 1 and dose 2 are being assessed 

separately. For this analysis, the 4 cases were all after the first dose.

Dr. Bernstein wondered whether the HepB vaccine that was given with the SHINGRIX was the 

new adjuvanted HEPLISAV-B

®

. His understanding was that there are no data regarding coadministration of two adjuvanted vaccines.

Dr. Shimabukuro said that he would have to check on that. There is very limited use of the new 

HEPLISAV-B

® vaccine except in one site that is conducting a post-marketing study for the 

manufacturer.

Ms. McNally said she was curious regarding the evaluation of other vaccines beyond HepB that 

may be given at or near the same time, and whether this was flagged as an issue with the GBS 

cases.

Dr. Shimabukuro indicated that there is intensive monitoring of influenza vaccines each season, 

as well as SHINGRIX. They certainly document co-administration, but are not specifically 

monitoring on co-administration. There is a period of intense enhanced monitoring after any 

newly licensed and recommended vaccine, and they will capture information when possible on 

co-administration. In VAERS, that is one of the 22 priority pre-specified conditions. Anytime RZV 

is co-administered with adjuvanted influenza vaccine, the new adjuvanted HepB vaccine, or all 

three together, those reports will be reviewed regardless of seriousness. Two of the cases had 

co-administration. One had PCV and the other HepB vaccine. However, co-administration has 

not been flagged specifically in the monitoring overall as problematic.

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Introduction

Kelly L. Moore, MD, MPH 

Chair, Hepatitis Vaccines WG 

Vanderbilt University School of Medicine 

Dr. Moore indicated that the terms of reference for the Hepatitis WG with respect to hepatitis A 

(HepA) are to: 1) update the HepA vaccine recommendations that were last comprehensively 

published in 2006 [ACIP Routine Recommendation for Hepatitis A Vaccine, MMWR 2006 May 

19;55(RR-7):1-23]; and 2) address persons living with HIV (PWHIV) as a risk group for HepA 

vaccination.

Recommendations published since October 2018 include the following:

❑

❑

Doshani M, Weng M, Moore K, Romero J, Nelson NP. Recommendations of the Advisory 

Committee on Immunization Practices for Use of Hepatitis A Vaccine for Persons 

Experiencing Homelessness. MMWR Morb Mortal Wkly Rep 2019;68:153-156.

Nelson NP, Link-Gelles R, Hofmeister MG, Romero JR, Moore KL, Ward JW, Schillie SF. 

Update: Recommendations of the Advisory Committee on Immunization Practices for Use of 

Hepatitis A Vaccine for Postexposure Prophylaxis and for Preexposure Prophylaxis for

International Travel. MMWR Morb Mortal Wkly Rep 2018;67:1216–1220. 

Between November 2018 and February 2019, the WG has convened four meetings focused on 

HIV as an indication for vaccination and has applied the EtR Framework and GRADE.

Dr. Moore indicated that during this ACIP meeting, members would hear presentations on 

PWHIV as a risk group for HepA vaccination with a vote at a future meeting. She first set the 

stage for this discussion in terms of why PWHIV should be considered for routine HepA 

vaccination, given that HIV alone does not increase the risk of exposure to HepA virus (HAV), 

nor does it necessarily lead to more severe disease. Studies suggest that HAV infection 

increases HIV replication in PWHIV. Studies also suggest that HIV infection delays HAV

infection resolution, which may lead to a longer period of transmissibility. Studies also suggest 

that PWHIV can mount a protective antibody response to vaccination, although that protection 

may be less robust.

The next steps for the WG include presenting the full updated HepA vaccine statement for a 

vote, and to continue its deliberations on adult HepB vaccination topics.

Hepatitis Vaccines

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Background: Hepatitis A among Persons Living with HIV

LCDR Mark Weng, MD MSc 

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

Centers for Disease Control and Prevention

Dr. Weng presented background information on HepA epidemiology; HepA vaccines; HAV 

ongoing outbreaks, including a small case study from Tennessee; and some statistics on HIV in 

the US. In 2016, there were 2007 reported cases. However, it is known that the reported cases 

will be much higher in 2017 and 2018 due to the ongoing HAV outbreaks in multiple states 

among people who use drugs and people experiencing homelessness.

1 When comparing the 

2016 HepA rates for all age groups, adults aged 20-49 years had the highest rates per 100,000 

population.

2 Overall data from the National Health and Nutrition Examination Survey (NHANES) 

show the prevalence of antibody among US residents is about 26.5% indicating that <1/3 of the 

US population had protection against HAV infection in 2009-2010. The lowest percentages of 

protection were among adults aged 30-49 years3[

1National Notifiable Diseases Surveillance 

System (NNDSS); Armstrong GL. Pediatrics 2007;119:e22-9; 2NNDSS, 

http://www.healthypeople.gov/2020/topicsobjectives2020/pdfs/Immunization.pdf; 3NHANES, 

National Health and Nutrition Examination Survey Murphy TV et al. Progress Toward 

Eliminating Hepatitis A Disease in the United States. MMWR Suppl. 2016 Feb 12;65(1):29-41].

Groups at increased risk of HAV infection or severe HepA disease are recommended to receive 

HepA vaccine. The recommended groups to receive HepA vaccine and year of recommendation 

are shown here:

❑

❑

❑

❑

❑

❑

❑

❑

❑

Travelers (1996)

Men who have sex with men (1996)

Users of injection and non-injection drugs (1996)

Persons with clotting-factor disorders (1996)

Persons who work with nonhuman primates (1996)

Persons with chronic liver disease (1996)

Persons who anticipate close personal contact with an international adoptee (2009)

Persons experiencing homelessness (2019)

Persons living with HIV (proposed)

This presentation regarding HIV and HepA vaccination focused on adults, since children are 

recommended for HepA vaccination as part of the routine childhood vaccination schedule at age 

12-23 months or as part of permissive catch-up vaccination. During licensing trials, it was found 

that HepA vaccines licensed in the US are highly immunogenic in immunocompetent persons 

aged greater than 18 years, when administered according to the recommended schedules. 

Protective antibody levels were identified in 94% to 100% of immunocompetent adults 1 month 

after the first dose. After the second dose, all immunocompetent persons had protective levels 

of antibody with high GMTs [Clemens R et al. J Infect Dis 1995;171(Suppl 1):S44–9.

Nalin DR. VAQTATM: hepatitis A vaccine, purified inactivated. Drugs of the Future 1995;20:24–

9. McMahon BJ, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska Native 

children and Native and non-Native adults. J Infect Dis 1995;171:676–9]. 

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In pre-licensure trials, adverse reactions to HAVRIX®, VAQTA®, and TWINRIX® were mostly 

injection site reactions and mild systemic reactions. Post-marketing surveillance for AEs

following receipt of HepA vaccines has been performed primarily by two systems in the US, 

VAERS and VSD. No unusual or unexpected safety patterns were observed for any of the HepA 

vaccines licensed in the US. More information on vaccine safety will be presented as part of the 

GRADE presentation [Vaccine Information Statement (VIS) 

https://www.cdc.gov/vaccines/hcp/vis/vis-statements/hep-a.htmlMMWR 2006;55(RR-7)].

In terms of immunogenicity, the antibody to HAV has been shown to persist in vaccine 

recipients for at least 20 years in immunocompetent adults administered inactivated vaccine as 

children with a 3-dose schedule.1 At least 20-year antibody to HAV persistence was 

demonstrated among immunocompetent adults vaccinated with a 2-dose schedule as adults.2

Detectable antibodies are estimated to persist for 40 years or longer based on mathematical 

modeling and antibody to HAV kinetic studies.2,3 Protection following natural infection is lifelong 

and may also be lifelong following vaccination. For persons with immunocompromising 

conditions or co-morbidities, protection may be less [

1Plumb ID, et al. J Viral Hepat. 2017 

Jul;24(7):608-612; 2Theeten H, et al. Vaccine. 2015 Oct 13;33(42):5723-7; 3Hens N, et al. 

Vaccine. 2014;32(13):1507-1513].

In adults the ≥2 doses vaccine coverage was much lower than in children and adolescents in 

2016 at 9.5% for adults ≥19 years, 13.4% for adults 19-49 years, and 5.4% for adults ≥50 years. 

When considering recommended risk groups for HepA vaccination, for adults aged 19-49 years, 

greater or equal to 2 doses vaccine coverage was 19% for Travelers and 24% for persons with 

chronic liver disease (CLD) [Vaccination Coverage Among Adults in the United States, National 

Health Interview Survey, 2016.https://www.cdc.gov/vaccines/imz-managers/coverage/

adultvaxview/NHIS-2016.html#hepA].

The epidemiology for HAV has shifted. In the past, large community outbreaks were associated 

with asymptomatic children infecting the adults who cared for them who then transmitted the 

virus to other adults. With widespread adoption of the universal childhood vaccination 

recommendations, asymptomatic children are no longer the main drivers of outbreaks. Although 

the overall incidence rate of HAV infection has decreased within all age groups, most adults are 

not immune because they have not been vaccinated and were not infected naturally. Older 

people are more likely to be symptomatic and experience severe disease and adverse 

outcomes such as hospitalization, fulminant liver disease, fulminant liver failure, and death. For 

the at-risk adults for which vaccination recommendations do exist, uptake is low. The number of 

cases has risen sharply since 2015. Person-to-person transmission is currently the most 

common source of HAV transmission in the ongoing outbreak [Collier M, et al. Hepatology 2015; 

Ly KN, Klevens RM. J Infect Dis 2015; Epson E, et al. Public Health, 2015; Murphy TV, et al. 

MMWR Suppl 2016; Foster M, et al. MMWR 2018].

HAV outbreaks have been ongoing in multiple states among people who use drugs and/or 

people experiencing homelessness, as well as continued reports of men who have sex with 

men (MSM) cases. Since these outbreaks were first identified in 2016, more than 13,000 cases 

and 7,400 hospitalizations have been reported, for a 57% hospitalization rate. Over 100 deaths 

have occurred nationwide because of these outbreaks. Hospitalization rates have been higher 

than typically associated with HAV infection, probably reflective of more serious illness among 

the vulnerable populations impacted by these outbreaks. HAV is highly transmissible from 

person-to-person, so prolonged community outbreaks have been challenging to control.

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This map shows in blue the 17 states that have been or are affected by the person-to-person 

HepA outbreaks:

Division of Viral Hepatitis Outbreak Website Map: 

https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm

During the course of the outbreak, multiple states reported cases among persons living with HIV 

who had a history of unknown or at least partial HepA vaccination. These reports prompted

CDC to request case reports from affected states and to perform a systematic review to 

investigate the risk of HAV infection and course of infection, and to evaluate the response to 

Hep A vaccine among persons living with HIV. Complete case information was not available 

from all states. Data from the Tennessee Department of Health were provided during this 

session.

In Tennessee, 14 persons living with HIV were infected with HAV. Of the 14, 5 (36%) were 

previously vaccinated with at least 1 dose of either combination or single-antigen HepA vaccine 

at least 1 month prior to hepatitis exposure. The other 8 had no or unknown vaccination history.

Of the 14, 13 (93%) had an indication for HepA vaccine prior to becoming ill with HAV. 

Previously vaccinated HAV cases among persons living with HIV raise concern about 

susceptibility to HAV among PWHIV and HepA vaccine long-term immunogenicity. These data 

represent missed opportunities for vaccination among persons with an existing recommended 

risk factor for vaccination of up to 8 patients (57%), and potential waning immunity among 

persons previously vaccinated of up to 43% [Courtesy: Julia Brennan and Tennessee 

Department of Health].

The following definition of HIV infection will be utilized:

The term refers to persons diagnosed with HIV infection, regardless of the stage of 

disease at diagnosis (i.e., HIV infection Stage 0, 1, 2, 3 [AIDS], or unknown), from all 50 

states, the District of Columbia, and 6 U.S. dependent areas (American Samoa, Guam, 

the Northern Mariana Islands, Puerto Rico, the Republic of Palau, and the U.S. Virgin 

Islands) [Centers for Disease Control and Prevention. HIV Surveillance Report, 2017; 

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vol. 29. http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. Published November 

2018. Accessed 2.19.2019].

At the end 2015, an estimated prevalence of 1.1 million people ≥13 years old were living with 

HIV infection, including 162,500 people (14.5%) whose HIV infection had not been diagnosed

[https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplementalreport-vol-23-1.pdf].

In 2017, the number of new HIV diagnoses was 38,739 and was mostly among adults. The 

highest numbers were among ages 20-39. CDC classifies HIV diagnoses into six transmission 

categories to which transmission may be attributed (perinatal transmission is not shown here):

The categories shown in red represent existing recommended risk groups for HepA vaccination.

Based on this classification, approximately 24% of persons living with HIV do not have another 

risk group for which HepA vaccination is recommended.

The Medical Monitoring Project (MMP) was used, which looks at a nationally representative 

sample of persons living with HIV, to answer the question, “What percentage of PWHIV do not 

have an existing risk factor for which HepA vaccine is recommended?” The percentage of 

persons living with HIV without a recommended risk group for HepA vaccination is higher when 

looking at more specific risk factor data. MMP includes the following risk groups for which HepA 

vaccination is recommended: MSM, injection and non-injection drug use, persons experiencing 

homelessness, chronic liver disease, and clotting factor disorders. Up to 40% of persons did not 

have a risk factor for which HepA vaccination is recommended. Some risk factors for which 

HepA vaccine is recommended could not be evaluated (e.g., occupational risk, travel risk, or 

exposure to an international adoptee from an endemic country). However, this illustrates that 

persons living with HIV might be missed for HepA vaccination if they do not have an existing 

factor for which HepA vaccine is recommended or they do not seek services for the other risk 

factors.

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In summary, HepA vaccine is largely responsible for the marked reduction in HAV cases. An 

increasing proportion of adults in the US are susceptible to HAV due to reduced exposure to 

HAV early in life, significant decreases in seroprevalence of anti-HAV antibody in older adults,

and because low two-dose vaccination coverage exists in adults, including high risk adults (e.g., 

travelers, or those with chronic liver disease). The ongoing HAV outbreaks illustrate the shifting 

epidemiology and person-to-person transmission among unvaccinated, vulnerable populations. 

About 1 million persons are living with HIV in the US. Finally, up to 40% of PWHIV HIV do not 

have a risk factor for which HepA vaccination is otherwise recommended.

GRADE: Use of HepA Vaccines Among Persons Living with HIV Infection

Alaya Koneru, MPH

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

Ms. Koneru presented on GRADE for HepA vaccine among PWHIV. This is an overview of the 

GRADE process, which is to:

❑

❑

❑

❑

❑

❑

❑

❑

❑

Develop policy questions

Consider critical outcomes

Review and summarize evidence of benefits and harms

Evaluate quality of evidence

Assess population benefit

Evaluate values and preferences

Review health economic data

Considerations for formulating recommendations

ACIP recommendation and GRADE category

The bolded bullets are the components followed by the WG for evaluation of HepA vaccine for 

PWHIV. The policy question for consideration was, “Should routine 2-dose vaccination vs. no 

routine vaccination to prevent HAV be given to adult HIV-positive persons regardless of another 

indication for vaccination?” The population of interest was adult HIV-positive persons regardless 

of another indication for vaccination. The intervention of interest was routine 2-dose HepA 

vaccination. The comparison of interest was no routine 2-dose HepA vaccination. The outcomes 

the WG considered and included in the evidence profile were HAV infection (designated as 

critical), mild AEs (designated as important), and SAEs (designated as critical).

For evidence retrieval, a systematic review was conducted of data on HepA vaccine and

PWHIV, including a search of Medline, EMBASE, CINAHL, Cochrane Library, and 

ClinicalTrials.gov through January 17, 2019. Search terms included: (((Hepatitis OR HAV OR 

hepatovirus) AND vaccin*) OR HepA OR Vaqta OR avaxim OR epaxal OR havpur OR Havrix 

OR nothav) AND (HIV OR human immunodeficiency). No language restrictions were placed on 

articles based on language or country of origin. Articles were excluded based on the following 

criteria: 

❑

❑

Articles focused solely on children or that did not have information on ages of included 

individuals

Articles with no data on HAVRIX® or VAQTA®, which are the two single antigen HepA 

vaccines currently licensed in the US

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❑

❑

❑

❑

Articles that that did not provide new data, only included safety data not in the target 

population of persons living with HIV infection, discussed vaccine introduction, made 

recommendations, or proposed guidelines 

Articles that could not be obtained full-text or in English

Articles on animals other than humans 

Clinical trials with no results available

A total of 927 unique abstracts were identified. Of these, 584 abstracts were excluded due to 

irrelevance. This left 343 articles for full-text review. Another 319 articles were eliminated due to 

irrelevance or publication prior to 1996, which was when HepA vaccine was introduced in the 

US. Studies also were excluded with populations that were a subset of other included studies. A 

total of 24 studies were included in the GRADE analysis.

In terms of reference values and corresponding units used throughout the presentation, for 

HepA vaccine, the correlate of protection is generally accepted to be 20 mIU/mL though this 

varies from 10 to 33 in the literature. There are two monovalent HepA vaccines licensed for 

adults in the US, VAQTA® and HAVRIX®. The dosage for VAQTA®is 50 units. The dosage for 

HAVRIX®is 1440 ELU. For the CD4 cell count, the normal range is 500 to 1500 cells/cells/mm3. 

Less than 200 cells/mm3indicates severely immunocompromised. For HIV viral load, 

undetectable is defined as HIV ribonucleic acid (RNA) less than 20 to 75 copies per mL 

depending upon the assay used.

The studies assessed for Outcome #1, HAV infection, varied in how data were collected and 

reported and the thresholds for seroconversion also varied by study. The Kemper 2003 study 

demonstrated that seroconversion was 68% among those with CD4 counts ≥200 and 9% 

among those with CD4 <200. This finding was significant. Launay 2008, a study from France, 

found in their ITT analysis that seroconversion was 69.4% among the 2-dose group and 82.6% 

among the 3-dose group. Wallace 2004, a US study, found an overall seroconversion of 94%, 

with 87% in the CD4 <300 group and 100% among the CD4 ≥300 group. Armstrong 2010, a US 

study, found a seroconversion rate of 60% overall, with 62.5% among those with CD4 >400 and 

55.56% among those with ≤400. Cheng 2017, a study from Taiwan, found a seroconversion rate

at month 12 of the study of 87.3% and 88.9% among those receiving 2- and 3-dose, 

respectively. Crum-Cianflone 2011, a US study, found an overall seroconversion of 89%, with 

78% among those with a CD4 <350 and 94% among those with CD4 ≥350. Horster 2010, a 

German study, found a seroconversion rate of 63.6%. Jablonowska 2014, a study from Poland, 

found a seroconversion rate of 79.5% after the second dose and immunogenicity of 75.5% 5 

years after vaccination.

Jimenez 2013, a US study, determined an overall seroconversion rate of 53.5% with 54% in the 

HAVRIX® group. Kourkounti 2012, a study from Greece, found a 74.4% seroconversion rate.

Kourkounti 2013 and 2014 found seroconversion rates of 77% and 76%, respectively. Lin 2018, 

a study from Taiwan, determined a seroconversion rate of 63.8% in their ITT analysis and 

93.7% in the per-protocol analysis. This study found an overall VE of 96.3%. Mena 2013, a 

study from Spain, found an overall seroconversion rate of 73.4%, with 80.7% in the HAVRIX®

group. Overton 2007, a US study, found a rate of 49.6% overall. Tsachouridou 2017, a study 

from Greece, found 80.7% seroconversion within 3 months of HepA series completion. Tseng 

2013, a study from Taiwan, found a 75.7% seroconversion rate among those receiving 2-dose 

vaccination. Weinberg 2012, a US study, found a 52% seroconversion rate in those who were 

HAV-seronaive and received vaccine. Weissman 2006, a US study, determined a 

seroconversion of 48.5%. Rimland 2005, a US study, found a rate of 60.7%. Valdez 2003, a US 

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study, found a rate of 88% among highly active antiretroviral therapy (HAART)-only recipients. 

Lederman 2003, a US study, found a seroconversion rate of 46%.

In terms of the studies assessed for Outcome #2, mild AEs, Kemper 2003 found that 1.6% of all 

subjects experienced severe headache, and 1.6% in the vaccine group experienced severe 

fatigue within 4 days of vaccination. Minor injection site soreness was found after 35% of 

vaccine doses were administered versus 8% of placebo doses administered. This study also 

found that reported post-vaccination bacterial, viral, and fungal infections was 24% versus 26%, 

among patients receiving vaccine versus placebo, respectively. Wallace 2004 reported local 

reaction at the injection site of 57% on the vaccine group versus 60% in the placebo group. 

Systemic AEs were predominantly headache and fever. Tseng 2013 reported mild tenderness 

at the injection site in 51.6% of all subjects within 24 hours of vaccination.

Regarding the studies assessed for Outcome #3, SAEs, Castro 2009, an RCT from Spain,

found that vaccinations in successfully treated PWHIV were safe, not associated with increased 

detectable viral load, and not associated with developing genotypic resistance mutations.

Horster 2010, a study from Germany, found that there were no adverse reactions after 

vaccination for those receiving HepA vaccination. No statistically significant difference between 

pre- and post-vaccination CD4 T-cell counts and HIV plasma load was observed in this study.

Launay 2008 found that there were no SAEs associated with vaccine and there were no 

significant changes in CD4+ T cell counts or plasma HIV-1 RNA levels. Bodsworth 1997 found 

no adverse outcomes attributable to vaccination. They also noted that there were no significant 

differences between the case and control groups for progression to AIDS, death, or mean CD4 

cell decline. Wallace 2004 determined that vaccination had no adverse effect on CD4 cell count 

or HIV viral load.

Moving the GRADE summary, the evidence types are displayed here for reference:

High/Evidence Type 1

We are very confident that the true effect lies close to that of the 

estimate of the effect.

Moderate/Evidence Type 2

We are moderately confident in the effect estimate: The true 

effect is likely to be close to the estimate of the effect, but there 

is a possibility that it is substantially different.

Low/Evidence Type 3

Our confidence in the effect estimate is limited: The true effect 

may be substantially different from the estimate of the effect.

Very low/Evidence Type 4

We have very little confidence in the effect estimate: The true 

effect is likely to be substantially different from the estimate of 

effect

The limitations of the articles described are that there were few studies that directly compared a 

standard 2-dose vaccination versus no vaccination in adult HIV-positive persons; there were 

limited studies with HAV infection as a study endpoint; and seroconversion thresholds for HepA 

antibodies and timing of the testing after vaccination varied by study.

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The benefit outcome, Hepatitis A Infection, for RCTs was graded as an Evidence Type 2. The 

WG downgraded for inconsistency due to variability of HepA antibody seroconversion 

thresholds used. The benefit outcome, HAV infection, for observational studies was graded as 

an Evidence Type 4. The WG downgraded for inconsistency due to variability of HepA antibody 

seroconversion thresholds used and for indirectness due to limited studies comparing a 2-dose 

standard intervention to no vaccine. The harm outcome, mild AEs, for RCTs was graded as an 

Evidence Type 1. The harm outcome, mild AEs, for observational studies was graded as an 

Evidence Type 3. The harm outcome, SAEs, for RCTs was graded as an Evidence Type 3. The 

WG downgraded indirectness for use of multiple non-HepA vaccines and for imprecision due to 

small study population size. The harm outcome, SAEs, for observational studies was graded as 

an Evidence Type 4. The WG downgraded indirectness for use of multiple non-HepA vaccines 

and for imprecision also due to small study population size.

ACIP EtR Recommendations Framework: Use of HepA Vaccines among PWHIV

LCDR Mark Weng, MD MSc 

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

Centers for Disease Control and Prevention

For the EtR framework, Dr. Weng reviewed the policy question and background and went 

through each of the 10 criteria, other considerations, balance of consequences, and ACIP 

recommendations. The policy question was, “Should routine two-dose vaccination vs. no routine 

vaccination to prevent HepA be given to HIV-positive adults, regardless of another indication for 

vaccination?” The 10 criteria are:

1. Is the problem a public health priority?

2. How substantial are the desirable anticipated effects?

3. How substantial are the undesirable anticipated effects?

4. Do the desirable effects outweigh the undesirable effects?

5. What is the overall certainty of the evidence for critical outcomes? GRADE

6. Does the target population feel that the desirable effects are large relative to the undesirable 

effects ?

7. Is there important uncertainty about or variability in how much people value the main 

outcomes?

8. Is the option acceptable to stakeholders?

9. Is the option a reasonable and efficient allocation of resources?

10. Is the option feasible to implement?

Dr. Weng noted that for the rest of this presentation, although the question refers to 2-doses, 

routine vaccination also can consist of a 3-dose schedule when combined HepA and B vaccine 

(Twinrix®) is administered.

Data suggest up to 87% of PWHIV are susceptible to HAV infection.

1-6 Of newly diagnosed 

PWHIV, 75% are at risk for HAV infection.

2 MMP shows that up to 40% of PWHIV had no 

indication for HepA vaccination.

7 Of HAV cases that did report risk factors, 56.2% indicated no 

risk factors for HAV.

8 Of note, nearly half (45.7%) of these HAV cases were missing data on risk 

factors for HAV [1DeGroote 2018; 2Moon 2018; 3Adejumo 2010; 4Sun 2009; 5Overton 2007; 

6Sheth 2006; 7CDC MMP 2016; 8CDC Viral Hepatitis Surveillance 2016].

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Criterion 1: Is the problem a public health priority?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

❑

❑

❑

❑

❑

❑

❑

PWHIV are at increased risk of HAV infection due to their immunocompromised state and 

missed opportunities for vaccination.1,2

Outbreaks that include PWHIV can have prolonged HAV transmission.3,4 HAV viremia in 

PWHIV tends to be higher and more durable.3

Infectious Disease Society of America (IDSA)

5 and 11 other review articles recommend or 

permissively recommend vaccinating all PWHIV.1, 6-15

Spain, Italy, and Australia report routinely vaccinating all PWHIV, at least in some parts of 

those countries.

16-20

[1. Koziel 2007; 2. Lin 2017; 3. Puoti 2012; 4. Yotsuyanagi et al, 1996; 5. Aberg 2013; 6. Crum-Cianflone 2014; 7. Pham 2011; 8. 

Crane 2009; 9. Kresina 2007; 10. Schiff 2007; 11. Brook 2006; 12. Gleeson 2006; 3. Sidiq 2006; 14. Laurence 2005; 15. Kwong 

1999; 16. Mena 2015; 17. Lugoboni 2012; 18. Turnbull 2011; 19. Rivas 2007; 20. Van Damme 2003].

Susceptibility in the HIV+ population is high, even among those with recommended risk factors 

for HepA vaccination. Several publications reporting on the HIV+ population showed that a 

substantial portion of PWHIV remain non-immune to HAV infection, including: 87% of high-risk 

patients at a New York HIV clinic, 58% at a Baltimore HIV clinic, 42% from the MMP, and 31% 

of active HIV clinic patients at Washington University. Where available, the characteristics of the 

HIV+ population, non-immune to HepA, are described. They are non-immune to HepA virus 

infection despite existing risk factors for HepA vaccination.

Criterion 2: How substantial are the desirable anticipated effects? (Beneficial effects of 

vaccination)

JUDGEMENTS:

 Minimal  Small  Moderate  Large  Don’t know  Varies

RESEARCH EVIDENCE:

HAV infection may increase HIV replication, potentially increasing HIV transmission.1

HAV infection in PWHIV is prolonged and can lead to longer transmission period.1-9

It is known that HepA vaccine is a highly effective vaccine in the general population.10

Seroconversion rates in PWHIV are 49.6%–94% from a 2015 published paper.

11 A similar 

range was seen in Ms. Koneru’s presentation.

1. Gallego 2011; 2. Lee 2018; 3. Ciccullo 2018; 4. Comelli 2018; 5. Lin 2017; 6. Ida 2005; 7. Laurence 2005; 8. Fonquernie 2001; 9. 

Lombardi 2019; 10. Fiore 2006; 11. Mena 2015

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Criterion 3: How substantial are the undesirable anticipated effects? (serious adverse 

events)

JUDGEMENTS:

 Minimal  Small  Moderate  Large  Don’t know  Varies

RESEARCH EVIDENCE:

❑ HepA vaccine is safe.1-3 The main side effect is mild, transient local soreness at the injection 

site based on follow-up of hundreds of millions of doses after 104 clinical studies in 27 

countries.

❑ There are similar rates of SAEs in PWHIV vs. HIV-negative persons,

4 with no unexpected 

vaccine AEs reported among PWHIV, 1990-2016.5

❑ HepA vaccine does not increase HIV viral load, CD4 cell count, or progression to AIDS.3,4,6-9

1. WHO 2013; 2. Fiore 2006; 3. André 2002; 4. Dlamini 2018; 5. Su 2018; 6. Phung 2012; 7. Shire 2006; 8. Kemper 2004; 9. 

Wallace 2003

Criterion 4: Do the desirable effects outweigh the undesirable effects?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

❑ Protection against HAV in PWHIV can be achieved, despite lower seroconversion rates in 

PAWHIV compared to persons without HIV.

1-3

❑ Out of 130 PWHIV, 85% maintained seropositivity 6-10 years after a 2-dose vaccine series.4

However, vaccination at higher CD4+ counts is associated with better vaccine-induced 

immune response, which supports vaccinating PWHIV earlier in the course of HIV 

diagnosis.

1,4-7

1. Mena 2015; 2. Crum-Cianflone 2014; 3. van Damme 2003; 4. Crum-Cianflone 2011; 5. Huang 2019; 6. Armstrong 2010; 7. 

Kemper 2003

Criterion 5: What is the overall certainty of the evidence for critical outcomes? GRADE

RESEARCH EVIDENCE: Outcome measures included in evidence profile just presented by Ms. 

Koneru:

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Criterion 6: Does the target population feel that the desirable effects are large relative to 

the undesirable effects?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

❑ Few have studied PWHIV preferences regarding HAV, expert opinion has been sought from 

select advocacy groups and from among the ACIP WG members who work clinically with 

the HIV population to arrive at the “Probably Yes” judgment.

❑ Qualitatively, frequent reasons for non-vaccination in one study were lack of 

recommendation by providers, lack of expected effectiveness, and fear of vaccine adverse 

effect.1

1. Zadeh 2010

Criterion 7: Is there important uncertainty about or variability in how much people value 

the main outcomes?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

❑ There are few studies specific to the PWHIV on valuing protection against HAV, but expert 

clinical opinion was sought to arrive at the “Probably No” opinion.

❑ Among people who use injection drugs (PWID), (of whom 24.2% were PWHIV), 

convenience was an important determining factor for initiating HepA/HepB vaccination.1

1. Campbell 2007

Criterion 8: Is the option acceptable to stakeholders?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

❑ There are parallels to the recommendations for HepB vaccination in PWHIV.1 Seroresponse 

is lower also with HepB vaccination for those with low CD4 counts. But, it is still 

recommended that all persons living with HIV receive their first dose of HepB vaccine during 

their first HIV care visit. Even though the vaccine is less immunogenic at lower CD4 counts, 

people at any CD4 count can and have responded.

❑ Routine HepA vaccination would be less confusing to clinicians than having a different 

approach for the two types of vaccinations.

1. J. Weiser 2019, communication. CDC Division of HIV/AIDS Prevention.

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Criterion 9: Is the option a reasonable and efficient allocation of resources?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE: 

❑

❑

❑

❑

❑

❑

Adult HepA vaccines are licensed only for certain high-risk groups, and cost-effectiveness 

data on its use for these indications are limited.1,2

It is known that outbreak campaigns incur high medical cost, productivity losses, disruption 

of other public health services, and diversion of public health resources and extensive 

human resources.3,4 For instance, the cost of a HepA outbreak among PWID (n=590, 

Washington) was $3.3 million. The cost of an outbreak among MSM (n=136, Ohio) was

$520,039.

1

The cost of routine immunization through HIV and primary care clinics may be lower per 

capita than cost of large, rapid vaccination campaigns for outbreak response.1-4

1. Luyten 2009; 2. O'Connor 1999; 3. Epson 2016; 4. Van der Hilst 2009

Criteria 10: Is the option feasible to implement?

JUDGEMENTS:

 No  Probably No  Uncertain  Probably Yes  Yes  Varies

RESEARCH EVIDENCE:

Simplifying provider guidance may improve protection of at-risk PWHIV.1,2

Vaccine response improves if PWHIV are vaccinated earlier in the course of HIV infection3, 

when patients have higher initial CD4 counts4-9 and lower HIV RNA viral load.6, 10, 11

Despite recommendations to vaccinate based on specific risk factors, there is inadequate 

screening and vaccination for HAV among PWHIV, even in HIV clinics.1, 5, 12 In a US study,

only 23.3% eligible outpatient PWHIV received 1 dose of HepA vaccine.

1

In a British study, 

HepA vaccine was indicated in 75% of PWHIV but had been delivered to 36% of eligible 

individuals.12

1. Tedaldi 2004; 2. Mena 2015. Medicina Clínica.; 3. Crum-Cianflone 2014; 4. Kemper 2013; 5. Kourkounti 2013; 6. Sell 2013; 7. 

Mena 2012; 8. Rimland 2005; 9. Wallace 2004; 10. Tseng 2013;11. Overton 2007; 12. Quinn 2012

In terms of other considerations, PWHIV may experience milder clinical course of HAV infection 

because of less immune response and liver injury, but infection is prolonged and can lead to a 

longer transmission period. Early small case series indicated persons living with HIV who 

became infected with HepA virus developed increased HIV viral load, increased liver enzyme 

levels, and significant declines in CD4 after pausing antiretroviral therapy (ART)

1-3

. Some of 

these small studies showed that HIV viral load increased in 38% of PWHIV with HAV infection,4

and that delayed resolution indicated by ALT remaining over 5 times the normal limit for over 2 

weeks after diagnosis of HAV infection.1 Larger recent studies showed less severe, but 

prolonged HAV course5-13. Host immune response may be the main pathogenic mechanism of 

liver injury in HAV.

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WG considerations regarding the factors favoring vaccination of PWHIV include the following: 

HAV infection may increase HIV replication, potentially increasing HIV transmission. Resolution 

of HAV infection may be delayed, potentially prolonging the infectious period. Up to 40% of 

PWHIV do not have a risk factor for which HepA vaccination is otherwise recommended. For 

PWHIV with an existing risk factor for HepA vaccination, another opportunity for vaccination 

would be provided for PWHIV who are missed or who do not seek services for other risk factors. 

Vaccine is safe and efficacious in PWHIV. 

WG consideration regarding the factors not favoring vaccination of PWHIV include the following: 

Illness from HAV infection may be less severe. Seroconversion may be lower or take longer 

among PWHIV vaccinated while they have low CD4 counts. Immunity may wane in PWHIV who 

have low CD4 counts. HIV infection alone is not a risk for HAV infection. 

In the balance of consequences, desirable consequences probably outweigh undesirable 

consequences in most settings. The WG does recommend that routine, 2-dose vaccination 

versus no routine vaccination to prevent HAV be given to adult persons with HIV, regardless of 

another indication for vaccination.

Future considerations if HepA vaccination is recommended for PWHIV are to consider 

additional protection with immunoglobulin and/or additional vaccine following a known high-risk 

exposure regardless of vaccination history, and consider periodic anti-HAV antibody testing 

and/or booster doses for persons with an ongoing risk for exposure, as with HepB. Data on VE 

among persons living with HIV should be evaluated for proximity of vaccination to HIV diagnosis

and CD4 count at vaccination and at exposure to HAV.

Discussion Points

To put this into perspective, Dr Nelson indicated that this pertains to about 1 million PWHIV up 

to 40% of whom do not have an existing risk factor for which HepA vaccine is currently 

recommended. Therefore, up to about 400,000 additional people would be recommended to 

receive HepA vaccine.

Dr. Bernstein wondered whether there would be any value in suggesting knowing laboratory 

criteria before administering the vaccine.

Dr. Nelson indicated that that would be a next step for WG discussion, but that she would say 

they would vaccinate at any CD4 count. However, persons who were vaccinated with a count 

lower than the cutoff would require data monitoring such as post-vaccination testing as is done 

for HepB vaccine.

Dr Romero pointed out that this also would mean that if ACIP makes this recommendation, at 

first contact with a healthcare provider, this would be an option. It would go into effect 

immediately such that newer populations would be immunized very early on rather than waiting 

for lower CD4 counts.

Dr. Fryhofer (AMA) thought the levels of 20 were antibody titers. In the past with her patients, 

she has checked qualitative antibody titers from time to time, but never a quantitative antibody 

titer. She wondered whether that came up in the review as something that practitioners should 

be checking to ensure that patients are immune.

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Dr. Nelson indicated that post-vaccination testing is not usually recommended. They do think 

that there is some waning of antibody as opposed to immunity, but this has been studied more 

closely in terms of HepB.

Dr. Atmar said his understanding was that the qualitative test is relatively less sensitive, so the 

threshold for being called “positive” is somewhat higher than the quantitative assays described 

in these studies. If someone is seropositive by qualitative test, they are likely to be above the 

threshold. If they are seronegative, it is uncertain. Regarding the comments about CD4 counts, 

of all of the studies that were shown the only one with a threshold of 200 had only a poor 9% 

seroconversion rate. Biologically, 200 has been a pretty important number. Therefore, he would 

want the WG to strongly consider recommendations with that in mind.

Dr. Lee observed that the question about public health burden is interpreted somewhat 

differently by different WGs. Perhaps something to consider would be how to consistently think 

about overall population burden as well as transmissibility, and whether individual health 

benefits should be considered as well. She understood why perhaps there is not a need for a 

formal cost-effectiveness analysis, but it would be helpful to get a sense of what the estimated 

cost would be of vaccinating the population and a smaller number of people, and “back of the 

envelope” calculations on disease burden averted and economic burden averted.

Dr. Messonnier said she was thinking the same thing. CDC will give thought to what that would 

look like so that they are not holding different groups to different standards, and perhaps work 

with the Economics WG to figure out what a “light” version would look like.

Ms. Hayes (ACNM) inquired as to how Dr. Weng’s data break down by gender. The risk factor 

for HepA is different in MSM than it is for women.

Dr. Weng replied that those data are available, Dr. Weiser added that they have not yet been 

analyzed, and Dr. Nelson agreed that they would present those data during the next meeting.

In terms of WG consideration around timing and CD4 counts, Dr. Moore thought they would 

want to assess this but it was not clear whether that would go into the vote or would be part of 

the additional clinical guidance in which CDC would provide more details. The WG is also 

cognizant of the fact that they need to harmonize with how HepB is handled in this population 

for whom HepB vaccine is also already recommended. There is a combination product that

contains both in a single injection that is an option. The WG will take these issues into 

consideration. She also pointed that that although economics is always very important to 

consider, it is very difficult to do with a disease that is outbreak-driven rather than being at a 

steady-state of exposure risk. While there is currently a large multi-state outbreak with certain 

communities at increased risk of exposure, that is why they presented outbreak costs as 

opposed to other general population costs the way that would be done with a disease that has a 

more steady state presentation.

Dr. Smith (ASTHO) noted that as the ATSHO representative and an HIV care provider, this 

would be very welcomed. Many HIV patients do have already defined risk factors, but because 

they are stigmatized conditions they oftentimes are not identified until much later. In the state 

HIV surveillance data for the most recent year, the largest category for risk factors is always 

“unknown” because it takes time to identify these risk factors. These individuals often have a 

payment source for their immunizations through the Ryan White Program. That is a way to get a 

relatively higher risk group for HepA immunized, because it is part of the system of care for 

them. In terms of timing and CD4 counts, this is an issue practitioners have to deal with for a 

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number of immunizations (pneumococcal, meningococcal, HepB, et cetera). Oftentimes, there is 

a clinical judgment in terms of when to give those. If there are compelling reasons to give them 

right away when the CD4 count is low, they are sometimes given.

Dr. Talbot looked at the Adult Immunization Schedule to determine whether HIV had its own 

column, which would make sense. But it is already purple, which means it should be 

considered. She wondered whether that meant it should be considered but not paid for. HepB is 

yellow, which is indicated. It would be beneficial to know what the vaccination rate is for HIV+ 

individuals to determine whether changing the color from purple to yellow would move that bar 

in the intended direction.

Dr. Cohn clarified that the purple bar on the high risk table means that if they have another 

indication, it is not contraindicated. That is, they can get it if they have another indication, but it 

does not mean that they should be considered because of the indication that is in the column.

Dr. Messonnier indicated that for the next meeting, they would commit to finding out the 

specifics in terms of reimbursement for those covered by Ryan White. From an immunization 

standpoint, if it is on the schedule, it is a recommended vaccine.

Dr. Cohn added that the color Dr. Talbot was talking about on that table was not a 

recommendation.

Dr. Moore said that for the State of Tennessee, there are a lot of quality metrics related to that. 

Dr. Carolyn Wester, Dr. Moore’s counterpart of Tennessee Department of Health, who is now 

the Director of CDC’s Division of Viral Hepatitis, always insisted on a quality of care indicator 

that was monitored at the state level for all HIV patients. Therefore, HepB vaccine completion 

was very high among HIV patients because they are tracked and cared for somewhat better 

than others with other risk factors.

Dr. Jeanne M. Santoli 

Immunization Services Division 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this session, Dr. Santoli presented an update on the HepB vaccines supply. She 

reported that Merck is not currently distributing its adult HepB vaccine or dialysis formulation 

and will not be distributing vaccine through the end of 2019. Together, GlaxoSmithKline (GSK)

and Dynavax have sufficient supplies of adult HepB vaccine to address the anticipated gap in 

Merck’s adult HepB vaccine supply during this period. However, preference for a specific 

presentation (i.e., vial versus syringe) may not be met uniformly during this time. This has not 

changed since the last update in October 2018.

Merck’s supplies of pediatric HepB vaccines have been constrained since mid-2017. Merck will 

continue to direct its limited supply to CDC to support utilization consistent with current clinical 

guidance. Merck expects to have a limited supply of monovalent HepB vaccine through 2019. 

This differs from the October 2018 update at which time a limited supply was predicted to be 

Vaccine Supply

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available through mid-2019. GSK is able to continue to cover the supply gap through 2019, with 

a combination of monovalent and combination vaccine. However, preference for a specific 

presentation (i.e., vial versus syringe) may not be met uniformly during this time period. The 

expected monovalent supply remains more than sufficient to cover the birth dose for all children, 

as well as some second and third doses.

As a reminder, CDC has a vaccine supply page that is kept updated in sync with all of the 

updates made during ACIP meetings. The Vaccine Supply/Shortage Webpage can be found at:

https://www.cdc.gov/vaccines/hcp/clinical-resources/shortages.html.

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Upon reviewing the foregoing version of the February 27-28, 2019 ACIP meeting minutes, Dr. 

Nancy Bennett, ACIP Chair, certified that to the best of her knowledge, they are accurate and 

complete. Her original, signed certification is on file with the Management Analysis and 

Services Office (MASO) of CDC.

Certification

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Department of Health and Human Services 

Centers for Disease Control and Prevention 

Advisory Committee on Immunization Practices 

November 2018 – June 30, 2019 

CHAIR

ROMERO, José R., MD, FAAP

Professor of Pediatrics

Horace C. Cabe Endowed Chair in Infectious Diseases

Director, Pediatric Infectious Diseases Section

University of Arkansas for Medical Sciences and Arkansas Children's Hospital 

Director, Clinical Trials Research

Arkansas Children's Hospital Research Institute

Little Rock, AR

Term: 10/30/2018-06/30/2021

EXECUTIVE SECRETARY

COHN, Amanda, MD

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Atlanta, GA

MEMBERS

ATMAR, Robert L., MD

John S. Dunn Clinical Research Professor in Infectious Diseases

Departments of Medicine and Molecular Virology & Microbiology 

Baylor College of Medicine 

Chief, Infectious Diseases Service

Ben Taub General Hospital, Harris Health System

Houston, TX

Term: 7/1/2016 – 6/30/2020

AULT, Kevin A., MD, FACOG, FIDSA 

Professor and Division Director

Department of Obstetrics and Gynecology

University of Kansas Medical Center 

Kansas City, KS

Term: 10/26/2018 – 6/30/2022

BERNSTEIN, Henry, DO, MHCM, FAAP

Professor of Pediatrics

Zucker School of Medicine at Hofstra/Northwell

Cohen Children’s Medical Center

New Hyde Park, NY

Term: 11/27/2017-06/30/2021

ACIP Membership Roster

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EZEANOLUE, Echezona, MD, MPH 

Professor of Pediatrics and Public Health

Department of Epidemiology and Biostatistics

Director, Global Health and Implementation Research Initiatives

University of Nevada

Las Vegas, NV

Term: 07/01/2015-06/30/2019

FREY, Sharon E., M.D.

Professor and Associate Director of Clinical Research

Clinical Director, Center for Vaccine Development

Division of Infectious Diseases, Allergy and Immunology

Saint Louis University Medical School

Saint Louis, MO

Term: 11/27/2017-06/30/2021

GRAVENSTEIN, Stefan, MD, MPH 

Professor of Medicine and Health Services Policy and Practice

Brown University

Associate Director, Center of Innovation for Long-Term Care Services and Supports

Providence Veterans Administration Hospital

Providence, RI

Term: 10/26/18 - 6/30/2022

HUNTER, Paul, MD

Associate Professor of Family Medicine and Community Health

University of Wisconsin School of Medicine and Public Health

Associate Medical Director 

City of Milwaukee Health Department

Milwaukee, WI

Term: 7/1/2016 – 6/30/2020

LEE, Grace M., MD, MPH

Associate Chief Medical Officer for Practice Innovation

Lucile Packard Children’s Hospital

Professor of Pediatrics, Stanford University School of Medicine

Stanford, CA

Term: 7/1/2016 – 6/30/2020

MCNALLY, Veronica V., JD

President and CEO

Franny Strong Foundation

West Bloomfield, Michigan

Term: 10/31/2018 – 6/30/2022

MOORE, Kelly, MD, MPH,

Assistant Clinical Professor, Department of Health Policy 

Vanderbilt University School of Medicine 

Nashville, TN

Term: 07/01/2015-06/30/2019

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STEPHENS, David, MD 

Professor of Medicine, Division of Infectious Diseases 

Chair, Department of Medicine 

Emory University School of Medicine 

Emory University 

Atlanta, GA 

Term: 07/01/2015-06/30/2019

SZILAGYI, Peter, MD, MPH 

Professor of Pediatrics

Executive Vice-Chair and Vice-Chair for Research

Department of Pediatrics 

University of California, Los Angeles (UCLA)

Los Angeles, California

Term: 7/1/2016 – 6/30-2020

TALBOT, Helen Keipp, MD

Associate Professor of Medicine

Vanderbilt University

Nashville, TN

Term: 10/29/2018 – 6/30/2022

WALTER, Emmanuel (Chip), Jr., MD, MPH

Professor of Pediatrics

Duke University School of Medicine

Durham, NC

Term: 07/01/2015-06/30/2019

EX OFFICIO MEMBERS

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth

Senior Policy Advisor

Division of Quality, Evaluations and Health Outcomes

Children and Adults Health Programs Group

Center for Medicaid, CHIP and Survey & Certification

Centers for Medicare and Medicaid Services

Baltimore, MD

Department of Defense (DoD)

DEUSSING, ERIC, MD, MPH

Commander, Medical Corps, United States Navy

Department of Defense Liaison

Centers for Disease Control and Prevention

Atlanta, GA

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Department of Veterans Affairs (DVA)

KIM, Jane A., MD, MPH

Deputy Chief Consultant for Preventive Medicine

Office of Patient Care Services

National Center for Health Promotion and Disease Prevention

Durham, North Carolina

Food and Drug Administration (FDA)

FINK, Doran, MD, PhD

Deputy Director, Clinical, Division of Vaccines and Related Products Applications

Office of Vaccines Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

Silver Spring, MD

Health Resources and Services Administration (HRSA)

NAIR, Narayan, MD

CAPT, USPHS

Division Director/Chief Medical Officer

Division of Injury Compensation Programs

Healthcare Systems Bureau

Rockville, MD

Indian Health Service (IHS)

WEISER, Thomas, MD, MPH

Medical Epidemiologist

Portland Area Indian Health Service

Portland, OR

National Vaccine Program Office (NVPO)

BECKHAM, Tammy

Acting Director

National Institutes of Health (NIH)

BEIGEL, John, M.D.

Associate Director for Clinical Research

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD

LIAISON REPRESENTATIVES

American Academy of Family Physicians (AAFP)

ROCKWELL, Pamela G., D.O.

Associate Professor, Department of Family Medicine,

University of Michigan Medical School

Medical Director, Dominos Farms Family Medicine

Ann Arbor, MI

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American Academy of Pediatrics (AAP)

MALDONADO, Yvonne, MD

Senior Associate Dean for Faculty Development and Diversity

Professor of Pediatrics and Health Research and Policy

Chief, Division of Pediatric Infectious Diseases

Stanford University School of Medicine

Stanford, CA

American Academy of Pediatrics (AAP)

Red Book Editor 

KIMBERLIN, David, MD

Professor of Pediatrics

Division of Pediatric Infectious Diseases

The University of Alabama at Birmingham School of Medicine

Birmingham, AL

American Academy of Physician Assistants (AAPA)

LÉGER, Marie-Michèle, MPH, PA-C

Senior Director, Clinical and Health Affairs

American Academy of Physician Assistants

Alexandria, VA

American College Health Association (ACHA)

EVEN, Susan, MD

Executive Director

Student Health Center

University of Missouri

Columbia, MO

American College of Nurse Midwives (ACNM)

HAYES, Carol E., CNM, MN, MPH

Lead Clinician

Clinical Quality Compliance and Management

Planned Parenthood Southeast 

Atlanta, GA

American College of Nurse Midwives (ACNM) (alternate)

MEHARRY, Pamela M., PHD, CNM

Midwifery Educator, Human Resources for Health

In partnership with University of Rwanda and University of Illinois, Chicago

American College of Obstetricians and Gynecologists (ACOG)

American College of Physicians (ACP)

GOLDMAN, Jason M. MD, FACP

Affiliate Assistant Professor of Clinical Biomedical Science, Florida Atlantic University, Boca 

Raton, Florida

Private Practice

Coral Springs, FL

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American Geriatrics Society (AGS)

SCHMADER, Kenneth, MD

Professor of Medicine-Geriatrics

Geriatrics Division Chief

Duke University and Durham VA Medical Centers

Durham, NC

America’s Health Insurance Plans (AHIP)

NETOSKIE, Mark J., MD, MBA

Market Medical Executive, CIGNA 

Houston, TX

American Immunization Registry Association (AIRA)

COYLE, Rebecca, MSEd

Executive Director, AIRA

Washington, DC

American Medical Association (AMA)

FRYHOFER, Sandra Adamson, MD

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Atlanta, GA

American Nurses Association (ANA)

RITTLE, Charles (Chad), DNP, MPH, RN

Assistant Professor, Nursing Faculty

Chatham University, School of Health Sciences

Pittsburgh, PA

American Osteopathic Association (AOA)

GROGG, Stanley E., DO

Associate Dean/Professor of Pediatrics

Oklahoma State University-Center for Health Sciences

Tulsa, OK

American Pharmacists Association (APhA)

FOSTER, Stephan L., PharmD

CAPT (Ret) U.S.P.H.S.

Professor, College of Pharmacy

University of Tennessee Health Sciences Center

Memphis, TN

Association of Immunization Managers (AIM)

FINLEY, Christine, RN, MPH 

Immunization Program Manager 

Vermont Department of Health

Burlington, VT

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Association for Prevention Teaching and Research (APTR)

McKINNEY, W. Paul, MD

Professor and Associate Dean

University of Louisville School of Public Health and Information Sciences

Louisville, KY

Association of State and Territorial Health Officials (ASTHO)

SMITH, Nathaniel, MD, MPH

Director and State Health Officer

Arkansas Department of Health

Little Rock, AR

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A., MBA

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy

Washington, DC 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD

State Epidemiologist

Office of Epidemiology, Food Protection and Immunization

Idaho Department of Health and Welfare

Boise, ID

Council of State and Territorial Epidemiologists (CSTE) (alternate)

LETT, Susan, MD, MPH

Medical Director, Immunization Program

Division of Epidemiology and Immunization

Massachusetts Department of Public Health

Boston, MA

Canadian National Advisory Committee on Immunization (NACI)

QUACH, Caroline, MD, MSc

Pediatric Infectious Disease Specialist and Medical Microbiologist 

Medical Lead, Infection Prevention and Control Unit 

Medical Co-director – Laboratory Medicine, Optilab

Montreal-CHUM

Montreal, Québec, Canada

Infectious Diseases Society of America (IDSA) 

BAKER, Carol J., MD

Professor of Pediatrics

Molecular Virology and Microbiology

Baylor College of Medicine

Houston, TX

National Association of County and City Health Officials (NACCHO)

ZAHN, Matthew, MD

Medical Director, Epidemiology

Orange County Health Care Agency

Santa Ana, CA

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National Association of County and City Health Officials (NACCHO) (alternate)

DUCHIN, Jeffrey, MD

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County

Professor in Medicine 

Division of Allergy and Infectious Diseases

University of Washington School of Medicine and School of Public Health

Seattle, WA

National Association of Pediatric Nurse Practitioners (NAPNAP)

STINCHFIELD, Patricia A., RN, MS, CPNP

Director

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota

St. Paul, MN

National Foundation for Infectious Diseases (NFID)

SCHAFFNER, William, MD

Chairman, Department of Preventive Medicine

Vanderbilt University School of Medicine

Nashville, TN

National Immunization Council and Child Health Program, Mexico

DURAN, Luis, MD

Director, Center for Children and Adolescent Health (CeNSIA)

Ministry of Health / Secretaría de Salud

Mexico

National Medical Association (NMA)

WHITLEY-WILLIAMS, Patricia, MD

Professor and Chair

University of Medicine and Dentistry of New Jersey

Robert Wood Johnson Medical School 

New Brunswick, NJ

Pediatric Infectious Diseases Society (PIDS)

O’LEARY, Sean, MD, MPH

Associate Professor of Pediatrics

Pediatric Infectious Diseases

General Academic Pediatrics

Children’s Hospital Colorado

University of Colorado School of Medicine

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD

Professor of Clinical Pediatrics

University of California, San Diego School of Medicine

San Diego, CA

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Pharmaceutical Research and Manufacturers of America (PhRMA)

ROBERTSON, Corey, MD, MPH 

Senior Director, US Medical, Sanofi Pasteur 

Swiftwater, PA

Society for Adolescent Health and Medicine (SAHM)

MIDDLEMAN, Amy B., MD, MSEd, MPH

Professor of Pediatrics

Chief, Section of Adolescent Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, OK

Society for Healthcare Epidemiology of America (SHEA)

WEBER, David, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology

University of North Carolina Schools of Medicine and Public Health

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care

University of North Carolina

Chapel Hill, NC

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